Donald School Embryo as a Person and as a Patient Asim Kurjak, Frank A Chervenak
Page numbers followed by f refer to figure and t refer to table.
Abdominal wall 59f
defects 52, 57, 58f
Abortion 41
risk of premature 121
Academia 30
Achondrogenesis 52
Acquired immunodeficiency syndrome 79
Acrania 52
Acrosome reaction 75
Adenomyosis 100, 100f
Adherence junction 3
Agnathia 54
Allele dropout 116, 117
Alobar holoprosencephaly 54f
Alpha-fetoprotein 124
Alzheimer's disease 136
American College of Obstetricians and Gynecologists 86
American Society for Reproductive Medicine 86
Amniocentesis 89
Amniochorionic membrane 16
Amniotic band syndrome, severe 52
Amniotic fluid 89
Anencephaly 52
Anovulation 101
Anthropology, developmental 30
Artificial intelligence, development of 138
Assisted reproductive
techniques 93, 97, 121
technology 19, 75
Astroglia 2
Atria 107
compare, large 107
Atrial septum primum 108
complete 108
Atrial spine 107
Atrioventricular canal 107
Atrioventricular endocardial cushions 108
Atrioventricular foramen 105
Atrioventricular junction 109
Auricle, malformations of 55
Autism 35
Autosomal trisomy 24
Bichorionic biamniotic triplets 123f
Big bang theory 30
Bioethical aspects 35
Biomedical technologies, current advancements of 12
Bio-optimists 131
Biopsy techniques 116
enlargement of 60
exstrophy 57
Blastocyst 44f, 75
inner cell mass of 15
removal 93f
stage 77
embryos 77
Blastomere 33
biopsy 77
Body mass index 101
Body plan, formation of 16
Body stalk anomaly 52, 57, 59
Bowel 58
changing appearance of 24f
develops 65
factories of 9
structure 51
vascularity, premature 22f
ventricle, single 54f
vesicles, primary 65
Butterfly sign 39f
Caenorhabditis elegans 16
Cajal-retzius cells 1, 6, 7
Cardiac activity, absent 124f
Cardiac defects, severe 52
Cardiac tube 106
Cardiac wall, three layered 108
Cardiogenic region 106
Carnegie stage 20t, 106110, 113
Catholic Church's teachings 41
number 77
theory 32
zygote, single 12
Central nervous system, fetal 65
Cerebellar plate 5f, 6f
Cerebellum 51
cortex 3
hemispheres 22
Cerebro-ocular-muscular syndrome 53
Chimera 40
Chorioepithelioma 41
Chorionic fluid, less 124f
Chorionic villus sampling 89, 90, 126
indications of 90
laboratory analysis of 92
risks of 91
training and audit of 92
Choroid plexus 9, 39f
Chromosomal defect 55
Chromosomal molecular analysis 92
Chromosomal risks 90
Chromosome 13, 125
screening platforms, comprehensive 116
Cleavage-stage scoring systems 77
Cleft lip 54
Cleft palate 54
Cognitive psychology, developmental 30
Color Doppler 56, 97
Communication skills 134
Cordocentesis 89
Coronary arteries 115
Coronary circulation 115
Corpus luteum 44, 44f
Corpus mamillare 5f
Cortical plate 2
formation of 8
Cortical reaction 75
Cranial bones, ossification of 52
Crown-rump length 53, 124
measurements 1
Cyclopia 54
Cystic fibrosis 93, 136
Cystic hygroma 56
Cysts, true 52
Dandy-Walker malformation 54
Darwinism, reception of 29
Decidualization phase 97
Democratic transhumanism 138
Deoxyribonucleic acid 92
analysis 90
Dialogue model 29
Diencephalon 9, 22, 51
Dimeric inhibin 124
Down syndrome 15, 124
Early pregnancy 52f
loss 96
Ears, low set 52, 55
Ear-shoulder distance, reduced 55f
Ectopia cordis 57
Egg activation 75
Electron microscopy 5
Embryo 12, 22f, 23f, 35, 66f, 67f, 84, 84, 109f, 112f
and yolk sac 21f
behavior of 65
cleavage-stage 77
coexistence of 40
crown-rump length of 108
culture medium, composition of 76
escapes 14
ethical concept of 82, 85
implantation 96
legal status of 38
length of 106, 110
moral status of 82
neurological development of 65
normal sonographic development of 51
single cell biopsy from 93f
to initiate pregnancy, transferring 85
to placenta-fetoplacental circulation 45
transfer 98, 121
visualization, normal 19
Embryology, modern 19
Embryonal pleural effusion 24
Embryonal stage
abnormalities 22
system 19
Embryonal vascularity 22f
Embryonic brain 22
Embryonic cardiac development 105
Embryonic development, staging of 1
Embryonic disk 40
Embryonic invasive diagnostic procedures 89
Embryonic lower limb 68f
Embryonic malformations 52
Embryonic movements 45
Embryonic period 9, 51, 53, 89
to adolescence 2f
Embryonic stage 114f
Embryonic stem cells 14
Embryonic upper limb 68f
Encephalocele 52, 53, 54f
Endocardial cushion fusion 110
Endocardial tube, paired 106
Endometrial cavity, central portion of 101f
Endometrial polyp 99f
Endometrial receptivity array 102
Endometrial volume, quantification of 97
Endometritis, chronic 96
Endometrium 96
chronic inflammation of 100
functional layers of 96f
myometrium border, loss of 100f
Enzymes 131
Epiblast 16
Epigenetics, influence of 34
Epiphysis 5f
Episcopic fluorescence imaging 105
Epithalamus 22
Ethics concept of person 84
Ethylenediaminetetraacetic acid 76
Euploid embryos 78
European Society of Human Reproduction and Embryology 86
Eventration 57, 58
Exencephaly 52
Extraembryonic membranes 15
Extropianism 138
Facial clefts 52
Facial malformations 54
Fertilization 12, 33, 40, 75
events of 75
steps 75
Fertilized oocyte to zygote 44f
Fetal abnormalities, early 51
Fetal activity 47f
Fetal anatomy 51
Fetal heads 55f
Fetal heart 57f, 58f
Fetal hydrops 56
Fetal malformations 52
Fetal period 52
Fetus 37f, 45f47f
first trimester 55f, 58f
side view of 56f
surface demonstration of 59f
with gastroschisis 58f
with hygroma colli 56f
with omphalocele 58f
Fluorescence in situ hybridization 116, 117
Follicle maturation 101
Foramen ovale 113, 115
Forebrain 3, 23f, 65
Four chambered heart 114f
Franceschetti syndrome 55
Ganglionic eminence 7f, 9
Gastroschisis 57
defects, sampling for single 92
disorders, single 78
Genetic hybridization, array comparative 92, 116
Genetic uniqueness 41
Genetic-obstetric counseling 89
Genetics, influence of 34
Genome 34
Genomic editing 131
designing baby with 135
Genomic hybridization 116
array comparative 117
Genotype 34
Germline gene 80
Gestational age 19, 105
Gestational sac, development of 20, 21f
Gestational twin sac, empty 127f, 128f
HDlive mode 51
HDlive technology 20
HDlive ultrasound 20
Heart defects 56
Heartbeat interruption 123f
Hematopoiesis 16
Hematopoietic stem cells 132
Hindbrain 23f, 65
Hippocampus 9
Holoprosencephaly 52, 53
Homologous recombination 131
Hormonal changes and implantation 101
Human being 31
Human blastocysts 15
Human chorionic gonadotropin 34, 90, 97
beta 55, 124
Human development
begins 33
visualization of early 43
Human embryo 1, 3f, 4f, 14, 136
powers of 12
Human embryogenesis, facts of 32
Human embryology 19
Human embryonic cortex 8
Human enhancement 131, 134
technologies 134
Human genome 34
editing 79
project 30, 34
Human life 31
beginning of 28, 32f, 39
Human person at fertilization 39, 40
Human superficial fetal cortex 5f
Human telencephalon 9f
Hybrid cell, single 33
Hydatidiform mole 41
Hydrops 52, 56
Hygromas 56
Hyperechogenic bowel 59
in fetus 59f
Hypoblast 16
Hypothalamus 22
Hysterosonography 98
Immortalism 138
Implantation 97, 100
assessment of abnormal 96
assessment of normal 96
In vitro embryo 85, 86
research with 86
In vitro fertilization 75, 84, 89, 98, 135
pregnancies 121
In vivo embryo 86
Inflammatory disease and implantation 98
Inner cell mass 75
Interventricular foramen 107109
closed 110
Interventricular septum, complete 110, 113
Intracavitary fibroid 98f
Intracavitary pathology 97
Intracranial translucency 56
Intracytoplasmatic injection 89
Intracytoplasmic sperm injection 121
Intradecidual gestational sac, small 44f
Intraembryonic circulation 45
development 1
embryonal death 26f
fetal death, early 24f, 26f
interventions 131
vascularity 21f
Invasive diagnostic sampling procedures 89
Invasive prenatal diagnosis 126
Ions, molecules of 13
Isthmus rombencephali 5f
Joubert syndrome 53
Kartagener syndrome 52
Karyotype analysis 90
Kidney 17
Kousseff syndrome 55
Kurjak Antenatal Neurodevelopmental Test 47f
Lamina affixa 9
Lamina terminalis 3f
Libertarian transhumanism 138
Life Protection Act 35
culture of 137
phenomenon of 30
anomalies 60
surface demonstration of 60f
defects 52
Liver 58
Living indefinitely long 139
Looping cardiac tube 106
Lower limb 71f, 73f
movements 70f, 71f
Luschka and magendie, foramina of 54
Luteal phase, late 97
Luteinizing hormone 15
Lymphatic malformation 56
Magnetic resonance microscopy 19
Mandible anomalies 55
Maternal blood sampling 90
Maternal serum markers 124
Mean sac diameter 51
Meckel's diverticulum 52
Meckel-Gruber syndrome 53
Medulla oblongata 51
Megacystis 52
Meganucleases 132
Memory enhancement 134
Mendelian diseases 92
Menstrual phase 96
endometrium 96f
Mesencephalon 3f, 51, 65
Mesenchyme 5f
Metabolism, errors of 90
Metencephalon 51
Microarray platforms 118
Microglia 2
Micrognathia 55
Midbrain 22f, 23f, 65
Mid-secretory phase 97
Mitochondria 80
Mitochondria manipulation 80
Mitochondrial genetic disorders 80
Mitochondrial genome 34
Molecular scissors 131
Monogenic disorders 78
Monogenic syndrome 54
Monozygotic twin phenomenon 40
Moral status, ethical concept of 84
Morphologic changes 106110, 113
Morula 75
aggregation 13
Multidimensional thinking 134
Multiple pregnancy 122
Muscular interventricular septum, complete 110
Mutism 35
Mycoplasma 100
Myelencephalon 5f, 51
Myometrial cysts 100f
Myometrium 100f
Nager syndrome 55
Nasal bone, absent 52
Natural philosophers 28
Neocortical cerebral wall, lamination in 4f
Neocortical development 2f
Neural crest cells 106
Neural tube defect, diagnosis of 56
Neuroepithelial stem cells 3, 4
Neuroepithelium 5f
Neurogenetic events, timing and sequence of 2f
Neuronal communication 6
Next generation sequencing 116118
Noninvasive prenatal screening 90, 125
Nonoverlapping magisteria principle 29
Nuchal translucency 124
enlarged 55, 55f
measurement 55
Nuclear genome 34
Nucleotide polymorphism, single 116, 117, 125
Obstetric ethics, professional 82
Obstetric management, counseling about 87
Obstetrics and gynecology, professional ethics in 82
Oligodendroglia 2
Omphalocele 57, 58
Omphalomesenteric duct cysts 52
One cell embryo 33
Oocyte 33
Optic vesicle 3f
Organogenesis 16
Ostium primum 107
closed 109, 110
Otocephaly 54
Ovum activation 33
Pallium 4
Parvovirus infection 56
Pelvic inflammatory disease 98
Perifollicular vascularization 43
Philosophy, developmental 30
Pierre-Robin syndrome, typical sign in 55
Placenta 44, 59f
Placental tissues 89
Plasma protein, pregnancy associated 55, 90, 124
Pleural effusion, bilateral 26f
Polycystic ovary syndrome 101
Polydactyly 52, 53
Polymerase chain reaction 77, 116, 117, 131
amplification analysis 92
quantitative 117
fluorescent 92
use of 116
Postconceptional weeks 1
Postconceptual week 3
embryo, sixth 5f
Postgenderism 138
Postovulation weeks 1
Pre-embryo 75
assessment 77
cryopreservation 76
culture conditions 75
development in vitro 75
genetic testing of 77
medical aspect 75
aspects 75
status of 79
Preimplantation genetic
diagnosis 77, 89, 92, 116, 117t
screening 77, 93, 116
testing 77, 78
Preimplantation testing 77
Preimplanted pre-embryo, legal status of 78
Prenatal diagnosis 131
Prenatal invasive techniques 89
Prezygote 40
Primitive atria 106
Primitive cardiac tube, single 106
Primitive endocardial cushion 107
Primitive ventricles 106
Primordial plexiform layer 1
Pronuclear scoring systems 77
Pronuclear transfer 80
Prosencephalon 22, 51, 65
Prune belly syndrome 60, 60f
Pseudocysts 52
Pseudodecidualization phase 97
Pseudostratified epithelium 3
Psychology, developmental 30
Radial artery blood flow 97f
Religious teachings, different 41
Renal abnormalities 53
Reproductive medicine 84
Retrognathia 52
Rhombencephalon 6f, 22, 51, 53, 65
Rigid biopsy forceps 91
Saline infusion sonography 98, 99f
three-dimensional 98f
Secretory phase, early 96
Semilunar valves 110
Senses 134
Septum primum 107
Sickle cell anemia 136
Singularitarianism 138
Sinus venosus 109f
Smith-Lemli-Opitz syndrome 55
Sonoembryology 19
three-dimensional 19
Sonographic study, two-dimensional 65
capacitation 75
oocyte binding 75
zona pellucida binding 75
Spermatozoa 31f, 32
Spina bifida 52, 56
small 57f
Spinal amiotrophy 93
Spinal canal, lower 57f
Spinal cord 3f
Spindle transfer 80
Spontaneous abortion 98
Spontaneous vermicular movements 65
Stoicism 35
Stomach 58
Strand breaks, double 131
Subpallium 4
thick basal portion of 7f
Subthalamus 22
Subventricular zone 1, 4
Sugars, molecules of 13
Sulcus monroi 9
Sulcus telodiencephalic 5f
Surviving twin 123
Syngamy 33
Tay-Sachs disease 93, 136
Technogaianism 138
Telencephalic vesicle 3f, 4f, 5, 5f, 6f, 9f
Telencephalon 3f, 7f
Temperature index 105
Termination of pregnancy 89, 93
counseling about 87
Thalamus 22
Thalassemia 93
Third ultrasound in first trimester 52
Thoracopagus 60f
Three-parent babies 80
Tortuous configuration 3
Traditional karyotype 92
Transabdominal chorionic villus sampling 90f, 91f
technique 90
Transcervical chorionic villus sampling technique 91
Transhumans, rights of 137t
Transvaginal imaging, two-dimensional 39f
Transvaginal sonography, two-dimensional 38f
Transvaginal ultrasound kidneys 59
Treacher-Collins syndrome 55
Trichorionic triamniotic triplets 122f
Tricuspid regurgitation 55
Trophectoderm tissue biopsy 116
Trophoblastic cells 93f
Truncal cushion 107
Truncus arteriosus 109
separation of 109
single undivided 107
Tubular heart 105f
Turner syndrome 56
conjoined 52, 60, 60f
pregnancy 121f, 126f
monoamniotic 60
monochorionic 60
in first trimester, three-dimensional 51
of septate uterus, three-dimensional 98f
scans, early 126f
three-dimensional 19, 51, 96
transvaginal three-dimensional 65
two-dimensional 61, 96
Umbilical artery
single 52, 59, 60, 61f
two 45
Umbilical cord 22f, 39f, 61f
cyst 52
prevalence of 52
middle of 53f
Umbilical cysts 52
Umbilical hernia 58
Umbilical vessels 59
Unconjugated estriol 124
Unfertilized oocyte 44f
Uniformly echogenic endometrium 97f
Upper limb 71f, 73f
left 69f
movements 70f, 71f
Upper lip, clefts of 54
Upper palate, clefts of 54
Ureaplasma urealyticum 100
Urinary tract anomalies 59
Uterine cavity 97
defects 97
upper half of 98f
Uterine circulation 97f
Uterine fundus, convex shape of 98f
Uterine receptivity, assessment of 101
Valve movements 110
Vanishing twin 25f
syndrome 121, 124, 126, 127
effects of 123
influence of 124126
Vasculogenesis 16
Vena cava valve 108
Ventricular cells 4
Vertebra, primary ossification of 56
Villous chromosomal examination 25f
Vitelline circulation 45
Vitrification method 76
Walker-Warburg syndrome 53
Warnock committee 78
Water, molecules of 13
Window of implantation 96
Wrist 71f
Xeroderma pigmentosum 132
Yolk sac 20, 22, 24, 37f, 66f, 67f, 69f73f
abnormality 52
echogenic shrunk 26f
large 24f, 25f
to embryo 45
Zagreb neuroembryological collection 3f
finger nucleases 132
sparks 75
Zona pellucida 33
penetration of 75
Zona reaction 75
Zygote 33
Chapter Notes

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Neurogenetic Processes in the Lateral Telencephalon during Intrauterine Development of the Human EmbryoCHAPTER 1

Ivica Kostović,
Iris Žunić Išasegi,
Željka Krsnik
Almost all functions which are characteristic for humans or make us human are integrated in the cerebral cortex. At the present, it is difficult to state when cerebral functions begin in a prenatal human brain and, and even more difficult to mark a crucial developmental phase in which humans begin to develop as cortical beings. Based on the fact that in the adult cortex all cortical functions are performed throughout chemical synapses, it is reasonable to propose that beginning of synaptogenesis in the human cortex marks an essential phase in development of human beings. As early as 1973, Molliver et al.1 presented evidence on synapses in a human telencephalon at 8.5 postconceptional weeks (PCW), at the beginning of fetal period. The rationale of this review is to discuss organization of the embryonic cortical anlage and embryonic precortical organization in human brain. In this review, we will discuss classical neuroembryological data, recent evidences on development of human embryological cortex, and our own data from previous papers, various textbook chapters,25 and Zagreb Neuroembryological Collection.6,7 Focus will be put on period from 6 to 7 postovulation weeks (POW) which roughly corresponds to 8–9 weeks of postmenstrual period. In our review, we will try to see whether there is something characteristic for human brain development in this late embryonic stage. Namely, organization of human embryonic brain is very similar to the monkey brain8 and early embryonic stages are very similar to development in other mammals. Human developmental neuroanatomists and neuroembryologists should answer the question if there is something in the organization of embryonic telencephalon that is characteristic for humans. It was already shown that some of the features of the human embryonic cortex are characteristic for the primate brains, such as an early appearance of Cajal-Retzius cells and subventricular zone (SVZ). Evaluating literature for this review, we have found that there is a lack of studies on histogenetic processes and development of connections and communication between neuronal cells. On the contrary, several current studies are focused on volumetric and other types of measurements of the developing cerebral vesicles during transitional period between embryo and fetus.911 In addition, contemporary researchers sometimes ignore classical developmental studies and present superficial interpretation of classical studies, e.g. seminal studies of His (1904)12 and precise atlas and reconstruction of Hochstetter's (1919).13
One of the serious issue in comparing embryological studies and clinical data is the problem of staging and timing of human embryos. For embryonic period, it is recommended to use postfertilization (postconceptional) age and embryological staging.8,14,15 Staging of embryonic development was systematically performed by Streeter1620 on the Carnegie Collection and systematically presented by O'Rahilly and his group.14,15,2124
In our review, we will use postconceptual age for embryonic period, but we will also refer to standard clinical timing (menstrual age—8.6 weeks). O'Rahilly and Gardner14 pointed out the fact that there is no menstruation age, because immediately after menstruation embryo does not exist.
In our Zagreb Neuroembryological Collection, we have used crown-rump length (CRL) measurements and careful histological analysis for evaluation of maturational phases, such as presence of embryonic zones, their development, and developmental status. Following the recommendation of O'Rahilly and Gardner,14 we express prospective developmental age as “at 20 mm CRL” instead of 20 mm stage.
Finally, there is a problem of terminology. Frequently used term for the late embryonic human cortex is “primordial plexiform layer” introduced by Marin-Padilla,25,26 based on the observation on developing cat, and not on developing human cortex. Term “plexiform” may be misleading because this layer situated between ventricular zone (VZ) or SVZ and pial surface is predominantly cellular, while only outer (toward pia) 2part is fibrillar or plexiform. This is properly described by His12 and is called mantle layer or Mantelschicht or intermediate zone. Recently, this compartment is called the “preplate” and this term is predominantly used by the current literature.5,27 For terminology, we recommend recent review by Bystron et al.27 with upgraded terminology of The Boulder Committee (1970)28 and Kostović and Judaš.5 However, we suggest that neuroembryological researchers compare current terminology and descriptions with classical descriptions of embryonic zones and terminology presented by His,12 The Boulder Committee,28 Kostović29 and O'Rahilly and Muller.24
In the present review, we will focus on the developmental period before formation of the cortical plate (CP), in order to discuss first cortical network in late embryonic human telencephalic wall with emphasis on status of histogenetic processes and intercellular communication though the intracellular junctions.3036 First, we will briefly describe histogenetic processes after appearance of telencephalic vesicles (4 PCW, stages 10-13), then we will discuss in extenso crucial phase of development at 20 mm CRL (7 PCW—corresponds to stage 20), and finally, we will describe the earliest appearance of the CP at 22–24 mm CRL (8 PCW), corresponding to stages 22 and 23.
Morphogenesis will be only briefly outlined and the focus will be on histogenetic status. Histogenetic events in the human embryonic and fetal cortex are following (Fig. 1.1)—neuronal proliferation and migration, glial proliferation, specification of morphological and molecular neuronal phenotypes (growth of dendrites, dendritic spines and axons), specification of glial morphological and molecular phenotypes (astroglia, oligodendroglia and microglia), aggregation of specific neuronal population, establishment of neuronal circuitry and connectivity (growth of axonal pathways and synaptogenesis), elimination of exuberant connectivity elements, and myelination.5 From the graphical presentation (Fig. 1.1), it is obvious that the main cellular histogenetic processes during embryonic period are—proliferation, migration, and molecular specification. End of the embryonic period starts with the process of neuronal aggregation into cytoarchitectonic zones, initial ingrowth and outgrowth of axons, and initial neurochemical maturation. The fact that intensity of different histogenetic events varies or may be even limited to certain developmental period is important in analysis of environmental and intrinsic factors on development of embryonic cortical anlage. Developmental periods with intensive occurrence of events may show increased vulnerability to adverse extrinsic and intrinsic pathogenetic influence and are usually described as sensitive or critical or vulnerable periods.
zoom view
Fig. 1.1: Timing and sequence of neurogenetic events in neocortical development from embryonic period to adolescence.Source: With permission from Elsevier.5
Cerebral cortex originates from the neuroepithelial cells in the wall of the paired telencephalic (endbrain) vesicles which develops on the each side of prosencephalon (forebrain) as early as 22 day postconception (2 mm length, stage 10), as shown in Figure 1.2 from the Zagreb Neuroembryological Collection. The telencephalic vesicle becomes visible during 4th embryonic week, 28 days (4 mm, stage 13, Fig. 1.3). During this period, thin wall of telencephalic vesicle consists of only one embryonic zone or lamina, the ventricular zone.2729 This zone is known as matrix or germinal epithelium or “primitive” ependyma. Ventricular zone is composed of immature neuroepithelial cells (neuroepithelial stem cells), which display elongated prismatic, polarized shape, radial orientation, and form single-layered neuroepithelium with cell nuclei positioned at the different distances from the cell pole (pseudostratified epithelium). One pole of this elongated neuroepithelial cells is in contact with ventricular (apical), ectodermal surface, while the other cell pole extends to the external mesodermal (basal) surface which is covered with basal membrane. These cells proliferate intensively and mitotic figures can be easily identified even on routinely stained histological sections. During the cell mitotic cycle, nuclei show characteristic “to and from” movement. More precisely, progenitor cells of VZ divide asynchronously during the DNA replication phase, and their nuclei move away from the ventricular surface and then move back to undergo another mitotic cycle.27 This process is called interkinetic nuclear movement. The neuroepithelial cells in the VZ (neuroepithelial stem cells) divide symmetrically, that is, after every division new proliferative cells are produced and number of proliferative neuroepithelial cells increases with concomitant growth of telencephalic vesicles. It is important to emphasize that neuroepithelial cells of VZ communicate and exchange signaling molecules via intercellular junctions at the apical (ventricular) pole. Two types of intracellular junctions are seen:37
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Fig. 1.2: Longitudinal section through the human embryo at 22nd postconceptional day (2 mm, stage 10) from the Zagreb Neuroembryological Collection. 1-Rostral neuroporus; 2-prosencephalon; 3-spinal cord.Source: With permission from Springer-Verlag.29
  1. Complex tight junction in tortuous configuration
  2. Adherence junction.
During the 5th week there is an increase in number of cells and thickening of VZ with further expansion of telencephalic vesicle. At this point, forebrain primordium and VZ are thicker in humans than in rodents.27 The most important cellular event at this period is the onset of asymmetrical division of some neuroepithelial stem cells—one cell remains progenitor, the other is a postmitotic cell destined to become neuron or glia.27 This is considered to be the beginning of neurogenesis! During this period, postmitotic neurons detach their apical pole from the VZ and together with most superficial processes of ventricular cells form a new cell-less densely packed zone which was originally called the intermediate zone (Fig. 1.4).12,28,29
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Fig. 1.3: The telencephalic vesicle becomes visible during 4th embryonic week, 28 days (4 mm, stage 13) 1- telencephalon; 2-optic vesicle; 3-lamina terminalis; 4-mesencephalon.Source: With permission from Springer-Verlag.29
However, due to the newly introduced concept of the “preplate” (Fig. 1.5), this zone is considered as a forerunner of preplate.5,27 Term “marginal zone” from this new terminology is reserved for the most superficial zone after formation of the CP (Fig. 1.5). The current neuroembryological studies have shown that elongated neuroepithelial stem cells have changed their property during neuroepithelial production. The most important cells generated by neuroepithelial cells are radial glial cells. This process is regulated by specific genes, such as Foxg1, Lhx2, Pax6 and Emx2.27 Radial glia serves two functions:
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Fig. 1.4: Cross-section through the telencephalic vesicles of human embryo at 16 mm—1-marginal zone; 2-intermediate zone; 3-ventricular zone.Source: With permission from Springer-Verlag.29
  1. As progenitor cells for production of neurons and glia
  2. As radial glia guide for neuronal migration.38
The next phase of embryonic development corresponds approximately to 6 postconceptual weeks (stages 17, 18, 19). In this phase, different portions of the cerebral wall show differences in thickness and cellular compositions. At this point, basic subdivisions of the telencephalic wall are much better macroscopically pronounced (Fig. 1.6) than in the earlier stages and first subdivision between thinner dorsal neuroepithelial wall (pallium) and basal portion (subpallium) is seen. The narrow portion of the telencephalon in the midline which is situated between two vesicles is very thin and is called telencephalon impar. In the dorsal wall (pallium), it is visible that medial telencephalon is thinner than the lateral telencephalon. In the medial telencephalic wall, the most interesting feature is the most ventral marginal part of the pallium where cerebral wall is slightly curved and shows clear enlargement of the marginal zone. This medial marginal (limbic) portion of telencephalon will differentiate into allocortex and curved part with the wide marginal zone (MZ) will differentiate into hippocampus.
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Fig. 1.5: Transient patterns of lamination in the neocortical cerebral wall from embryonic (A, B) to late fetal period (G).Source: With permission from Elsevier.5
[VZ: ventricular zone; SVZ: subventricular zone; PP: preplate; SP: subplate zone; MZ: marginal zone; CP: cortical plate; IZ: intermediate zone (fetal “white” matter)]
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Fig. 1.6: Reconstruction model of the CNS of the 6th postconceptual week embryo (11 mm, stage 17). 1-isthmus rombencephali; 2-cerebellar plate; 3-epiphysis; 4-myelencephalon; 5-corpus mamillare; 6-sulcus telodiencephalic; 7-telencephalic vesicles.
Anlage of hippocampus is characterized by enlargement of MZ, which remains characteristic throughout development.
At the very limbus, the cerebral wall is transformed into thin epithelial lamellae (area epithelialis of lamina tectoria), which stretches from one telencephalic vesicle to another. At the transitional zone between margin of pallium (of telencephalic vesicles) and area epithelialis, one single-layer portion of lamina epithelialis invaginates in the cavity of ventricles and forms anlage of plexus choroideus. First primitive blood vessels appear outside the epithelia. Since there are no blood vessels within telencephalic portion of the neuronal tube, it was proposed that metabolically necessary nutrients have access to neuroepithelium from the liquor inside neural tube—telencephalic anlage or via extracellular fluid outside the neuroepithelium.37,39 During the 6th week, mesenchyme envelops of the telencephalic vesicle differentiates into pia mater. Primitive vessels penetrate through pia mater in the neuroepithelial wall of the telencephalic vesicles. As a first step in this process, there is an accumulation of collagen fibrils at the external surface of the basal membrane and primitive blood vessels become aligned on the external surface of the telencephalic vesicles. In the second phase, fibroblasts appear between basal membrane—collagen layer on the side of neuroepithelium and blood vessels sheet on the other (mesenchymal) side. In the third phase, blood vessels covered with basal membrane and collagen fibrils penetrate into the wall of telencephalic vesicles. Thus, by the end of embryonic period all structures of pia mater are developed: basal membrane, layer of collagen fibrils, layer of fibroblasts and blood vessels. Below the basal membrane, there are end feet of neuroepithelial cells which are poorly differentiated. At this early developmental point, it is difficult to answer whether these immature end feet below basal membrane and around vessels belong to the universal type of neuroepithelial cells or do they belong to glia. At the end of embryonic period and the beginning of fetal period, end feet became well differentiated, show electron microscopy (EM)-lucent features, may be filled with glycogen-rich granules, and belong to specialized glia cells (Fig. 1.7).
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Fig. 1.7: Electron micrograph of the human superficial fetal cortex, after formation of the CP, at 9 PCW showing EM-lucent glycogen-loaded end feet of specialized (radial) glia. At the interface of neuroepithelium and mesenchyma, following elements can be seen: glia (asterisk), basal membrane (three arrows), collagen fibrils (two arrows) and fibroblasts (one arrow).
During this phase of embryonic period (6 postconceptual weeks), many postmitotic cells lose their attachments to apical (ventricular) surface in order to move–migrate toward pial (basal) surface and form a new embryonic zone, properly described by His,12 called mantle layer or Mantelschicht, Zwischenschicht or intermediate zone.12,28,29 However, due to the concept of preplate, currently, this zone is known as the term “preplate”.5,27 After formation of the preplate, telencephalic wall consists of VZ and preplate (two-laminar composition). However, preplate can be further divided in the mantle layer and marginal zone, and this phase can be described as three-laminar cerebral wall. At this point, we would like to point out to general rules of neurogenesis—all neurons are produced (born) on places which are different than 6their final position in the adult brain. That means that all cells must migrate in order to reach their final position. The distances for migration of neurons during embryonic period are much shorter and mechanisms of neuronal detachment and migration were not described for human cortex. In fetal period, when the distances for migration are extremely long (more than 1 cm), mechanisms of radial migration along radial glia were documented in 1972 by Rakic.38
Formation of the next zone, proliferative SVZ, during the end of 6 PCW is a crucial event for human cortical histogenesis. The SVZ is composed of proliferative progenitor cells which have lost attachment with ventricular surface and moved outward in basal (pial) direction. Some of the cells from VZ move tangentially and show polymorphic shape, while other maintained connection with basal surface. SVZ is particularly well developed in primate cortex and seems to be as a fountainhead of some neuronal population, such as projection neurons and calretinin interneurons which are characteristic for primate—human brain organization. The importance of SVZ zone as a second proliferative zone in a primate cortex was first described by Rakić.40 In current developmental neurobiology, SVZ of midgestational fetal human cerebrum is considered as an essential fountainhead of cortical neurons and a key player in the production of complex, large gyrencephalic human brain.41,42 It is very likely that neuron production in SVZ begins already in embryonic period. However, we have proposed that the real impulse for the neuronal production in the SVZ begins in the early fetal life (between 8 PCW and 10 PCW) when major afferent system from thalamus and basal forebrain interact with progenitor cells in SVZ.43
Histogenetic Events and Cytoarchitectonic Organization of Embryonic Brain at 20 mm Crown-rump Length
At 7th week, telencephalic vesicles have increased in their size and dominate the picture of external morphology of the embryo (Fig. 1.8). Please note gradual thinning of cerebral wall from thick basolateral portion to the thin dorsolateral portion (Figs. 1.9 to 1.11). Analysis of these semi-thin sections therefore reveals the following regions of the lateral telencephalon:
  • Dorsolateral
  • Midlateral
  • Basolateral.
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Fig. 1.8: Whole embryo at 22 mm CRL. Please note increased size of telencephalic vesicle (1). Rhombencephalon is still exposed and cerebellar plate (2) is clearly seen. (3) Marks fourth (IV) ventricle.Source: With permission from Springer-Verlag.29
The most important histogenetic event is the enlargement of the preplate (mantle layer) in the basolateral portion (Fig. 1.9C). Preplate shows two different sublaminas with different orientation and packing density of the cells. Deeper portion close to SVZ is characterized by the high density of cells, and superficial portion appears more fibrillar with lower cell density. The organization of preplate in two laminas is less obvious at:
Fine cytological analysis of one micron-thick plastic sections reveals large cells which are oriented parallel to pia matter, presumably immature Cajal–Retzius cells (Fig. 1.9B asterisk). Similar relationship is seen on more posterior level (Fig. 1.10). Please note enlarged blood vessels which form primordial plexus external of the basal membrane (Figs. 1.10A to C, arrows). These vessels are not regular arteries and veins, but form plexus resembling cavernous veins. There are also numerous vessels which start to form subventricular plexus within the telencephalic wall. Progressive diminishment in the preplate size is well seen in Figure 1.11. Proofs of intensive proliferative activity at this developmental period are numerous mitotic figures (Figs. 1.9A and B, arrows). The pale appearance in the ventricular zone close to ventricular surface is due to the densely packed apical processes of ventricular and eventually subventricular cells (Fig. 1.11, asterisk).
Neuronal communication and circuitry elements at 20 mm—synapses, axons, and postsynaptic elements. In our EM study, we have performed systematic analyses of the whole thickness of the telencephalic wall and we have not found typical synapses characterized by membrane-associated pre- and postsynaptic densities and synaptic vesicles.447
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Fig. 1.9: Cross-section through the telencephalon, through the future foramen interventriculare, shows thick basal portion of subpallium with ganglionic eminence (low magnification on the left). Squares indicate position of large magnification shown in figures a, b, c. Arrows (a, b) indicate mitotic figures in the VZ. Asterisk marks prospective Cajal–Retzius neuron in the superficial portion of mantle-preplate layer. Scale bar = 100 µm.(MZ: marginal zone; PP: preplate; SVZ: subventricular zone; VZ: ventricular zone)
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Fig. 1.10: Cross-section through the telencephalon on more posterior level than in Figure 9, showing thick basal portion of subpallium with ganglionic eminence (low magnification on the left). Squares indicate position of large magnification shown in figures a, b, c. (1) marks diencephalon. One arrow indicates pial blood vessels; two arrows indicate SVZ blood vessels. Scale bar =100 µm.(MZ: marginal zone; PP: preplate; SVZ: subventricular zone; VZ: ventricular zone)
Thus, we have not confirmed observation of Larroche45 about presence of synapses in 7-week-old embryo. However, we have found numerous intercellular junctions through preplate-mantle layer, but very few gap junctions. Gap junctions are equivalent of electrical synapses30,37 and are supposed to be ultrastructural bases of oscillatory nonsynaptic activity of the developing cortex. Based on the absence of synapses and paucity of gap junctions, it seems that other nontypical transient junction, as well as increased extracellular space or extracellular matrix are crucial substrate of Ca2+ signaling and communication via processes.3036,4648
The communication between preplate neurons and first differentiated glia may occur via classical transmitters, which are secreted and diffused through extracellular matrix and act on other cells without involvement of synapses and junctions.49 The most likely source of early transmitter synthesis and release are prospective GABAergic neurons which begin to develop at the early fetal development.5054 The most remarkable population of early neurons are forerunners of large Cajal–Retzius cell, which are reelin–positive and there are some evidence about their glutamatergic nature.558
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Fig. 1.11: Progressive diminishment of the preplate size is well seen along the hemispheric curvature. Asterisk marks tightly packed apical processes of proliferative cells. Scale bar = 100 µm.(MZ: marginal zone; PP: preplate; SVZ: subventricular zone; VZ: ventricular zone)
However, it is not clear at what exact moment do they become synapticly engaged, and what are their postsynaptic elements in the early fetal cortex. Furthermore, the data on early gliogenesis are incomplete; even though it was well documented that microglia were found in intracerebral structures as early as 6 weeks of gestation.56 Other types of glia develop eventually early,57 but the exact onset of their earliest appearance is not determined at this moment.
In conclusion, human embryonic cortex at 20 mm CRL displays remarkable human characteristic features of proliferative zones, presence of postmigratory neurons, and first nonsynaptic communication via intercellular junctions and/or extracellular matrix-rich environment. Morphologically, all parts of brain may be clearly recognized and prominent telencephalic vesicles are result of intensive proliferation in VZ and SVZ, and initial migration.
Formation of Cortical Plate at 22/24 mm, Transition between Embryonic and Fetal Period (8 PCW, Stages 22/23)
During transition between embryonic and fetal period, the first postmitotic and postmigratory neurons settle in the most superficial zone of the preplate and form one layer of densely-packed cells, so called CP. The CP formation is considered to be crucial event in histogenesis of cerebral cortex in both classical12,14,58 and current literature.29,52 CP appears in basolateral portion of telencephalic vesicle, in a form of disc-like shape, latter extends along the hemisphere and by 8.5–9 weeks of postconception, all parts of neocortex contain cell-dense CP. This event marks the beginning of the cortical gray matter development. Below the CP, there is a thin plexiform disrupted layer—presubplate (PSP) zone of Kostović and Rakic.59 Above the CP, there is a cell-poor marginal zone which contains Cajal–Retzius cells, apical branching of CP cells and axons. Thus, after formation of the CP, at the end of embryonic period, cortex consists of three layers: MZ, CP, and PSP. At the very beginning, some neurons (pioneering) form initial pioneering CP.52 The earliest formation of CP was described by His12 and is also visible on the cross sections through the human telencephalon at 20 mm CRL embryos-fetuses shown in Hochstetter atlas13 (Fig. 1.12). Neuronal organization of the CP was described by Kostović-Knežević et al.60 CP is built by immature neurons which have bipolar shape of cell body, but they develop apical bouquet in the MZ and root-like arborization on their basal side. One of these processes of root-like arborization is an immature axon which is already directed toward IZ. Early CP cells are densely packed and form, so called, embryonic columns.61
Parallel with the formation of immature CP between 8 weeks and 8.5 weeks, there is a first appearance of synapses characterized by membrane-associated presynaptic and postsynaptic vesicles and synaptic vesicles.1 This crucial event in the earliest human fetal cortex during transition between embryonic and fetal period was emphasized by our group in many articles.59,629
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Fig. 1.12: Earliest formation of CP is seen on the cross sections though the human telencephalon at 20 mm CRL embryos-fetuses from Hochstetter atlas (1919). Arrow indicates CP in a form of initial disc in the basolateral portion of telencephalic vesicles. (Pl. ch.: choroid plexus; Hi.: hippocampus; L.a.: lamina affixa; Z.H.: diencephalon; S.M.: sulcus Monroi; G.H.: ganglionic eminence)
Here we emphasize the fact that this event marks the beginning of humans as cortical beings. From that point, human immature cortical compartments (MZ, CP, and PSP) are incorporated in early synaptic network. Significance of human fetus as a patient and early cortical functions were extensively discussed in numerous publications edited by Kurjak and Chervenak,63 Chervenak, Kurjak and Comstock64 and Pooh and Kurjak.65 It is notable that synapses were found above and below CP and that cell-dense CP is synapse-free until 24 PCW. Significance of this bilaminar distribution of synapses (below and above CP) is not clear, but it obviously corresponds to the early maturing cells of presubplate and MZ, and apical bouquets of CP neurons. When early synapses were first described, they were interpreted as transient synapses1,59 and their functional significance was not known. Transient early synapses may underlie different patterns of fetal behavior, which can show continuity throughout fetal life.66,67 However, subsequent experimental studies have confirmed that early synapses are important constituents of early endogenous, spontaneous activity.6874 Impairment of spontaneous activity may have far-reaching consequences for the cortex development.47,70
  • Second half of embryonic period (4–8 PCW) is a critical developmental window for telencephalic vesicles development, which is neuroepithelial fountainhead for development of human cortex. Three histogenetic processes dominate in this period of early development:
    • Proliferation of neurons and glia in the ventricular and subventricular zones (“factories” of the brain)
    • Early migration of postmitotic cells in the preplate (mantle) zone
    • Molecular specification with transient activity of different genes.
Telencephalic vesicles (anlage of cerebral vesicle) are composed of pluripotent neuroepithelial cells (stem cells), which are polarized and contact apical (ventricular) and basal (pial) surface during the earliest phases. At 20 mm CRL, two human-characteristic histogenetic events take place:
  1. Formation of SVZ as a fountainhead of associative cortical neurons and interneurons
  2. Formation of preplate as a forerunner of CP and subplate (SP).
Early embryonic cortical cells communicate through nonsynaptic junctions and extracellular space. First synapses are formed after formation of the CP, around 8 PCW, and show bilaminar distribution: deep synaptic stratum below CP, in the presubplate and superficial synaptic stratum in the MZ, above CP. Onset of synaptogenesis around 8 PCW marks the beginning of human life as cortical beings. Nonsynaptic and synaptic junctions of the embryonic or early fetal cortex underlie spontaneous endogenous activity and present basic framework for cortical development. Therefore, it can be predicted that if different extrinsic and intrinsic pathogenetic factors act during late embryonic period, it will cause major abnormalities of cerebral wall structure and laminar organization of the cerebral cortex.
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