Neural - Cerebrum Development

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Human embryo developing cortex (week 8, stage 22)
Human cerebrum and underlying ventricular development imaged by MRI[1]
Dev anat 01.jpg

The brain (cerebral cortex) as it is generally recognised. Though the cerebrum includes the cerebral cortex and the subcortical structures (hippocampus, basal ganglia, and olfactory bulb). The adult cerebral cortex like other neural structures has a laminar organisation, the mammalian neocortex consists of six layers, while the reptilian and avian cortices have only three layers (equivalent to mammalian layers I, V and VI).

A simplified developmental sequence can be described as cell proliferation, cell migration, and finally cortical organization. In development, lamination occurs in an "inside-out" sequence earlier inside and later born neurons outside. The cortex is divided into areas which serve distinct functions including motor, sensory and cognitive processing. The lamination process requires a range of different signals including; Reelin (Reln, an extracellular protein), Disabled-1 (Dab1, an intracellular signaling molecule), and Cullin-5 (Cul5, an E3 ubiquitin ligase).

The cortex progenitor cell types are either neuron-restricted or bipotent (neuron-glial) progenitors that generate glial-restricted progenitors at mid- and late neurogenesis.

Neural Parts: neural | prosencephalon | telencephalon cerebrum | amygdala | hippocampus | basal ganglia | lateral ventricles | diencephalon | Epithalamus | thalamus | hypothalamus‎ | pituitary | pineal | third ventricle | mesencephalon | tectum | cerebral aqueduct | rhombencephalon | metencephalon | pons | cerebellum | myelencephalon | medulla oblongata | spinal cord | neural vascular | meninges | Category:Neural
Neural Links: neural | ventricular | ectoderm | Stage 22 | gliogenesis | neural fetal | Medicine Lecture - Neural | Lecture - Ectoderm | Lecture - Neural Crest | Lab - Early Neural | neural crest | Sensory | neural abnormalities | folic acid | iodine deficiency | Fetal Alcohol Syndrome | Postnatal | Postnatal - Neural Examination | Histology | Historic Neural | Category:Neural

Some Recent Findings

  • The LPA-LPA4 axis is required for establishment of bipolar morphology and radial migration of newborn cortical neurons[2] "Neurons in the developing neocortex undergo radial migration, a process that is coupled with their precise passage from multipolar to bipolar shape. The cell-extrinsic signals that govern this transition are, however, poorly understood. Here, we find that lysophosphatidic acid (LPA) signaling contributes to the establishment of a bipolar shape in mouse migratory neurons through LPA receptor 4 (LPA4)."
  • Development of the sensorimotor cortex in the human fetus: a morphological description[3] "Twenty-one human fetal brains from 13 to 28 gestational weeks were studied macroscopically to describe the morphological stages of sulcal and gyral development in the sensorimotor cortex....Four chronological stages of sensorimotor cortex development were defined: stage 1: appearance at 18-19 gestational weeks (GWs) of the inferior part of the central cerebral sulcus; stage 2: development of the pericentral lateral regions and the beginning of opercularization at 20-22 GWs; stage 3: development of parietal and temporal cortices and the covering of the postcentral insular region at 24-26 GWs; and finally stage 4: maturation of the central cerebral regions at 27-28 GWs."
More recent papers  
Mark Hill.jpg
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This table shows an automated computer PubMed search using the listed sub-heading term.

  • Therefore the list of references do not reflect any editorial selection of material based on content or relevance.
  • References appear in this list based upon the date of the actual page viewing.

References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability.

Links: References | Discussion Page | Pubmed Most Recent | Journal Searches

Search term: Cerebral Cortex Embryology

Isis Trujillo-Gonzalez, Yanyan Wang, Walter B Friday, Kasey C Vickers, Cynthia L Toth, Lorian Molina-Torres, Natalia Surzenko, Steven H Zeisel microRNA-129-5p is regulated by choline availability and controls EGF receptor synthesis and neurogenesis in the cerebral cortex. FASEB J.: 2018;fj201801094RR PubMed 30521373

Hamid M Abdolmaleky, Adam C Gower, Chen-Khuan Wong, Jiayi W Cox, Xiaoling Zhang, Arunthathi Thiagalingam, Rahim Shafa, Vadivelu Sivaraman, Jin-Rong Zhou, Sam Thiagalingam Aberrant transcriptomes and DNA methylomes define pathways that drive pathogenesis and loss of brain laterality/asymmetry in schizophrenia and bipolar disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet.: 2018; PubMed 30468562

Francesca Cargnin, Ji-Sun Kwon, Sol Katzman, Bin Chen, Jae W Lee, Soo-Kyung Lee FOXG1 Orchestrates Neocortical Organization and Cortico-Cortical Connections. Neuron: 2018; PubMed 30392794

Taichi Hara, Ikuko Maejima, Tomoko Akuzawa, Rika Hirai, Hisae Kobayashi, Satoshi Tsukamoto, Mika Tsunoda, Aguri Ono, Shota Yamakoshi, Satoshi Oikawa, Ken Sato Rer1-mediated quality control system is required for neural stem cell maintenance during cerebral cortex development. PLoS Genet.: 2018, 14(9);e1007647 PubMed 30260951

Gina E Elsen, Francesco Bedogni, Rebecca D Hodge, Theo K Bammler, James W MacDonald, Susan Lindtner, John L R Rubenstein, Robert F Hevner The Epigenetic Factor Landscape of Developing Neocortex Is Regulated by Transcription Factors Pax6→ Tbr2→ Tbr1. Front Neurosci: 2018, 12;571 PubMed 30186101

Older papers  
These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table.

See also the Discussion Page for other references listed by year and References on this current page.

  • Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero[4] "we applied recent advances in fetal MRI motion correction and computational image analysis techniques to 40 normal fetal human brains covering a period of primary sulcal formation (20-28 gestational weeks). Growth patterns were mapped by quantifying tissue locations that were expanding more or less quickly than the overall cerebral growth rate, which reveal increasing structural complexity. We detected increased local relative growth rates in the formation of the precentral and postcentral gyri, right superior temporal gyrus, and opercula, which differentiated between the constant growth rate in underlying cerebral mantle and the accelerating rate in the cortical plate undergoing folding. Analysis focused on the cortical plate revealed greater volume increases in parietal and occipital regions compared to the frontal lobe. Cortical plate growth patterns constrained to narrower age ranges showed that gyrification, reflected by greater growth rates, was more pronounced after 24 gestational weeks. Local hemispheric volume asymmetry was located in the posterior peri-Sylvian area associated with structural lateralization in the mature brain."
  • Development of laminar organization of the fetal cerebrum[5] "Heads of 131 fetal specimens of 14-40 weeks gestational age (GA) were scanned by 3.0T MRI. Eleven fetal specimens of 14-27 weeks GA were scanned by 7.0T MRI. On T(1)-weighted 3.0T MRI, layers could be visualized at 14 weeks GA and appeared clearer after 18 weeks GA. On 7.0T MRI, four zones could be recognized at 14 weeks GA. During 15-22 weeks GA, when laminar organization appeared typical, seven layers including the periventricular zone and external capsule fibers could be differentiated, which corresponded to seven zones in histological stained sections. At 23-28 weeks GA, laminar organization appeared less typical, and borderlines among them appeared obscured. After 30 weeks GA, it disappeared and turned into mature-like structures. The developing lamination appeared the most distinguishable at the parieto-occipital part of brain and peripheral regions of the hippocampus. The migrating thalamocortical afferents were probably delineated as a high signal layer located at the lower, middle, and upper part of the subplate zone at 16-28 weeks GA on T(1)-weighted 3.0T MRI."
  • Correlation of diffusion tensor imaging with histology in the developing human frontal cerebrum[6] "Transient early cerebral laminar organization resulting from normal developmental events has been revealed in human beings through histology and imaging studies. DTI studies have postulated that the fractional anisotropy (FA)-based differentiation of different laminar structures reflects both differing cellular density over the glial fibers and fiber alignment in respective regions. The aim of this study was to correlate FA values in these transient zones with histology. Brain DTI was performed on 50 freshly aborted human fetuses with gestational ages (GA) ranging from 12 to 42 weeks. Regions of interest were placed on the cortical plate, subplate, intermediate and germinal matrix (GMx) zones of the frontal lobe to quantify FA values. Glial fibrillary acidic protein (GFAP), neurofilament (NF) and neuron-specific enolase (NSE) immunohistochemical analyses were performed for the cortical plate, intermediate zone and GMx. In the cortical plate, a significant positive correlation was observed between FA values and percentage area of GFAP expression in fetuses <or=28 weeks of GA (r = 0.56, p = 0.01). FA values showed a significant positive correlation with the percentage area of NF expression in the intermediate zone (r = 0.54, p = 0.05). A significant positive correlation was also observed between FA and the number of NSE-positive cells per mm(2) in the GMx (r = 0.76, p < 0.01) and subplate (r = 0.59, p = 0.03) zones. The results of our study suggest that the FA can be used as noninvasive marker of neurodevelopmental events in the frontal lobe of human fetal brain."

Development Overview

Neuralation begins at the trilaminar embryo with formation of the notochord and somites, both of which underly the ectoderm and do not contribute to the nervous system, but are involved with patterning its initial formation. The central portion of the ectoderm then forms the neural plate that folds to form the neural tube, that will eventually form the entire central nervous system.

Early developmental sequence: Epiblast - Ectoderm - Neural Plate - Neural groove and Neural Crest - Neural Tube and Neural Crest

Neural Tube Primary Vesicles Secondary Vesicles Adult Structures
week 3 week 4 week 5 adult
neural plate
neural groove
neural tube

Prosencephalon Telencephalon Rhinencephalon, Amygdala, Hippocampus, Cerebrum (Cortex), Hypothalamus, Pituitary | Basal Ganglia, lateral ventricles
Diencephalon Epithalamus, Thalamus, Subthalamus, Pineal, third ventricle
Mesencephalon Mesencephalon Tectum, Cerebral peduncle, Pretectum, cerebral aqueduct
Rhombencephalon Metencephalon Pons, Cerebellum
Myelencephalon Medulla Oblongata
Spinal Cord

Early Brain Vesicles

Primary Vesicles

CNS primary vesicles.jpg

Secondary Vesicles

CNS secondary vesicles.jpg

Late Embryonic Brain

Stage 22 image 217.jpg

Human embryo developing cortex (Week 8, Carnegie stage 22)

  • small embryo shows approximate level of section.
  • insert top right shows whole head section.
  • small shaded box on whole section shows region of large image.
  • layer thicknesses are shown in microns.

Early Fetal Brain

Human- fetal week 10 head A.jpg Human- fetal week 10 head B.jpg
Human- fetal week 10 head C.jpg Human- fetal week 10 head D.jpg

The above images are from a week 10 human fetus.

Fetal Brain

Gray0654.jpg Gray0655.jpg Gray0658.jpg
Fetal brain (3 months) Fetal brain (4 months) Fetal brain (5 months)

Fissures are the major indentations, sulci (singular sulcus), that divide the brain surface into lobes and appear during fetal development as the brain grows. The images below show MRI analysis of the developing human fetal brain.

Brain fissure development 01.jpg

Brain fissure development 02.jpg

Brain fissure development 03.jpg

Links: Magnetic Resonance Imaging

Developmental Overview


Cortical Neurons

Telencephalon development signals[7]

Neural- cortex Cajal drawing 01.jpg

Cortical layers in a historic drawing by Cajal.

Brain histology 01.jpg

Adult mouse cortex

I molecular layer - few neurons and mainly of extensions of apical dendrites and horizontally-oriented axons.

II external granular layer - small pyramidal neurons and many stellate neurons.

III external pyramidal layer - mainly small and medium-size pyramidal neurons, some non-pyramidal neurons with vertically-oriented intracortical axons.

IV internal granular layer - different types of stellate and pyramidal neurons.

V internal pyramidal layer - large pyramidal neurons.

VI multiform layer - few large pyramidal neurons and many small spindle-like pyramidal and multiform neurons.

Cajal-Retzius Neurons

Cajal-Retzius (CR) cells are some of the earliest generated cortical neurons arising from restricted domains of the pallial ventricular zone, and then migrate from the borders of the developing pallium to cover the cortical primordium. These early forming neurons then control the radial migration of neurons and the formation of cortical layers. In mice, this has been shown by these cells secreting the extracellular glycoprotein Reelin (Reln) and it has been suggested that these cells also fine tune multiple signaling pathways underlying the regulation of cortical regionalization.[7]


Mouse adult cortex[8]
  • Fgfr1 and Fgfr2 - control excitatory cortical neuron development within the entire cerebral cortex.[9]
  • Fgfr2 - proper formation of the medial prefrontal cortex (mPFC).[9]
  • MARCKS - (myristoylated alanine-rich C-kinase substrate protein) a cellular substrate for PKC modulates radial glial placement and expansion.[10]
  • MicroRNA - noncoding RNAs that regulate mRNA expression, highly expressed during development.[11]
  • Wnt - contribute to the production of basal progenitors (non-surface dividing or intermediate progenitors).[12]

Corpus Callosum

The corpus callosum is the area of the brain which connects the two cerebral hemispheres. Maximum increase in thickness and width of the corpus callosum occurred between 19 and 21 weeks' gestation.[13]

Human Timeline:

  • 74 days - callosal axons appear.
  • 84 days - subdivisions of the genu and splenium can be identified.
  • 115 days - adult morphology is seen.

Agenesis of Corpus Callosum

Agenesis of the corpus callosum (ACC) is a partial or complete absence of the corpus callosum, a rare cerebral malformation.

Links: NINDS Information

Cerebral Vascular Development

Overview cartoon Early vascular changes
Cerebral brain artery development 01.jpg Cerebral brain artery development 01.jpg

Chronological development of cerebral brain arteries initially with the rise of the internal carotid artery and subsequently with the development of the posterior circulation.[14]

Links: Blood Vessel Development | Head Development


Agenesis of Corpus Callosum

Agenesis of the corpus callosum (ACC) is a partial or complete absence of the corpus callosum, a rare cerebral malformation.

Links: NINDS Information


Increased proliferation


Ectopic migration


A malformations derived from abnormal neuronal migration leading to agyria (convolutions of the cerebral cortex are not fully formed) and pachygyria (convolutions of the cerebral cortex unusually thick ).

Pachygyria (Greek, pachy = "thick")


Decreased proliferation


Abnormal organization, numerous small gyri and a thick disorganized cortical plate lacking normal lamination, disruption of microtubule-based processes underlies a large spectrum of neuronal migration.[15]


Abnormal organization


  1. Habas PA, Kim K, Rousseau F, Glenn OA, Barkovich AJ & Studholme C. (2010). Atlas-based segmentation of developing tissues in the human brain with quantitative validation in young fetuses. Hum Brain Mapp , 31, 1348-58. PMID: 20108226 DOI.
  2. Kurabayashi N, Tanaka A, Nguyen MD & Sanada K. (2018). The LPA-LPA4 axis is required for establishment of bipolar morphology and radial migration of newborn cortical neurons. Development , 145, . PMID: 30217809 DOI.
  3. Afif A, Trouillas J & Mertens P. (2015). Development of the sensorimotor cortex in the human fetus: a morphological description. Surg Radiol Anat , 37, 153-60. PMID: 24972575 DOI.
  4. Rajagopalan V, Scott J, Habas PA, Kim K, Corbett-Detig J, Rousseau F, Barkovich AJ, Glenn OA & Studholme C. (2011). Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero. J. Neurosci. , 31, 2878-87. PMID: 21414909 DOI.
  5. Zhang Z, Liu S, Lin X, Teng G, Yu T, Fang F & Zang F. (2011). Development of laminar organization of the fetal cerebrum at 3.0T and 7.0T: a postmortem MRI study. Neuroradiology , 53, 177-84. PMID: 20981415 DOI.
  6. Trivedi R, Husain N, Rathore RK, Saksena S, Srivastava S, Malik GK, Das V, Pradhan M, Pandey CM & Gupta RK. (2009). Correlation of diffusion tensor imaging with histology in the developing human frontal cerebrum. Dev. Neurosci. , 31, 487-96. PMID: 19622880 DOI.
  7. 7.0 7.1 Amélie Griveau, Ugo Borello, Frédéric Causeret, Fadel Tissir, Nicole Boggetto, Sonia Karaz, Alessandra Pierani A novel role for Dbx1-derived Cajal-Retzius cells in early regionalization of the cerebral cortical neuroepithelium. PLoS Biol.: 2010, 8(7);e1000440 PubMed 20668538 | PLoS Biol.
  8. P Berbel, D Navarro, E Ausó, E Varea, A E Rodríguez, J J Ballesta, M Salinas, E Flores, C C Faura, G Morreale de Escobar Role of late maternal thyroid hormones in cerebral cortex development: an experimental model for human prematurity. Cereb. Cortex: 2010, 20(6);1462-75 PubMed 19812240 | PMC2871377
  9. 9.0 9.1 Hanna E Stevens, Karen M Smith, M Elisabetta Maragnoli, Devon Fagel, Erzsi Borok, Marya Shanabrough, Tamas L Horvath, Flora M Vaccarino Fgfr2 is required for the development of the medial prefrontal cortex and its connections with limbic circuits. J. Neurosci.: 2010, 30(16);5590-602 PubMed 20410112
  10. Jill M Weimer, Yukako Yokota, Amelia Stanco, Deborah J Stumpo, Perry J Blackshear, E S Anton MARCKS modulates radial progenitor placement, proliferation and organization in the developing cerebral cortex. Development: 2009, 136(17);2965-75 PubMed 19666823
  11. Sarah K Fineberg, Kenneth S Kosik, Beverly L Davidson MicroRNAs potentiate neural development. Neuron: 2009, 64(3);303-9 PubMed 19914179
  12. Atsushi Kuwahara, Yusuke Hirabayashi, Paul S Knoepfler, Makoto M Taketo, Juro Sakai, Tatsuhiko Kodama, Yukiko Gotoh Wnt signaling and its downstream target N-myc regulate basal progenitors in the developing neocortex. Development: 2010, 137(7);1035-44 PubMed 20215343
  13. R Achiron, A Achiron Development of the human fetal corpus callosum: a high-resolution, cross-sectional sonographic study. Ultrasound Obstet Gynecol: 2001, 18(4);343-7 PubMed 11778993
  14. Khaled Menshawi, Jay P Mohr, Jose Gutierrez A Functional Perspective on the Embryology and Anatomy of the Cerebral Blood Supply. J Stroke: 2015, 17(2);144-58 PubMed 26060802 | J Stroke.
  15. Xavier Hubert Jaglin, Karine Poirier, Yoann Saillour, Emmanuelle Buhler, Guoling Tian, Nadia Bahi-Buisson, Catherine Fallet-Bianco, Françoise Phan-Dinh-Tuy, Xiang Peng Kong, Pascale Bomont, Laëtitia Castelnau-Ptakhine, Sylvie Odent, Philippe Loget, Manoelle Kossorotoff, Irina Snoeck, Ghislaine Plessis, Philippe Parent, Cherif Beldjord, Carlos Cardoso, Alfonso Represa, Jonathan Flint, David Anthony Keays, Nicholas Justin Cowan, Jamel Chelly Mutations in the beta-tubulin gene TUBB2B result in asymmetrical polymicrogyria. Nat. Genet.: 2009, 41(6);746-52 PubMed 19465910


Alejandro L Diaz, Joseph G Gleeson The molecular and genetic mechanisms of neocortex development. Clin Perinatol: 2009, 36(3);503-12 PubMed 19732610

Pasko Rakic Evolution of the neocortex: a perspective from developmental biology. Nat. Rev. Neurosci.: 2009, 10(10);724-35 PubMed 19763105


Jinfeng Zhan, Ivo D Dinov, Junning Li, Zhonghe Zhang, Sam Hobel, Yonggang Shi, Xiangtao Lin, Alen Zamanyan, Lei Feng, Gaojun Teng, Fang Fang, Yuchun Tang, Fengchao Zang, Arthur W Toga, Shuwei Liu Spatial-temporal atlas of human fetal brain development during the early second trimester. Neuroimage: 2013, 82;115-26 PubMed 23727529

Lorelei D Shoemaker, Nicholas M Orozco, Daniel H Geschwind, Julian P Whitelegge, Kym F Faull, Harley I Kornblum Identification of differentially expressed proteins in murine embryonic and postnatal cortical neural progenitors. PLoS ONE: 2010, 5(2);e9121 PubMed 20161753

Céline Zimmer, Jun Lee, Amélie Griveau, Silvia Arber, Alessandra Pierani, Sonia Garel, François Guillemot Role of Fgf8 signalling in the specification of rostral Cajal-Retzius cells. Development: 2010, 137(2);293-302 PubMed 20040495

Sergi Simó, Yves Jossin, Jonathan A Cooper Cullin 5 regulates cortical layering by modulating the speed and duration of Dab1-dependent neuronal migration. J. Neurosci.: 2010, 30(16);5668-76 PubMed 20410119

Hanna E Stevens, Karen M Smith, M Elisabetta Maragnoli, Devon Fagel, Erzsi Borok, Marya Shanabrough, Tamas L Horvath, Flora M Vaccarino Fgfr2 is required for the development of the medial prefrontal cortex and its connections with limbic circuits. J. Neurosci.: 2010, 30(16);5590-602 PubMed 20410112

Atsushi Kuwahara, Yusuke Hirabayashi, Paul S Knoepfler, Makoto M Taketo, Juro Sakai, Tatsuhiko Kodama, Yukiko Gotoh Wnt signaling and its downstream target N-myc regulate basal progenitors in the developing neocortex. Development: 2010, 137(7);1035-44 PubMed 20215343

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  • Zagreb Neuroembryological Collection - contains more than 500 prenatal human brains stained with various classical neurohistological, as well as modern histochemical and immunohistochemical methods. The bank is located at the Croatian Institute for Brain Research.

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