Development of the cerebral cortex

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The development of the cerebral cortex, known as corticogenesis is the process during which the cerebral cortex of the brain is formed as part of the development of the nervous system of mammals including its development in humans. The cortex is the outer layer of the brain and is composed of up to six layers. Neurons formed in the ventricular zone migrate to their final locations in one of the six layers of the cortex. [1] The process occurs from embryonic day 10 to 17 in mice and between gestational weeks seven to 18 in humans. [2]

Contents

The cortex is the outermost layer of the brain and consists primarily of gray matter, or neuronal cell bodies. Interior areas of the brain consist of myelinated axons and appear as white matter.

Cortical plates

Preplate

The preplate is the first stage in corticogenesis prior to the development of the cortical plate. The preplate is located between the pia mater and the ventricular zone. According to current knowledge, the preplate contains the first-born or pioneer neurons. These neurons are mainly thought to be Cajal-Retzius cells, a transient cell type that signals for cell migration and organization. [3]

Subplate

Visualization of corticogenesis in the mouse. The 6 cortex layers migrate from the ventricular zone through the subplate to come to rest in the cortical plate (layers 2 through 6) or in the marginal zone (layer 1) Corticogenesis in a wild-type mouse with captions in english copy.png
Visualization of corticogenesis in the mouse. The 6 cortex layers migrate from the ventricular zone through the subplate to come to rest in the cortical plate (layers 2 through 6) or in the marginal zone (layer 1)

The preplate also contains the predecessor to the subplate, which is sometimes referred to as a layer. As the cortical plate appears, the preplate separates into two components. The Cajal-Retzius cells go into the marginal zone, above the cortical plate, while the subplate moves inferior to the 6 cortical layers. [1]

Appropriate functioning and development of the subplate is highly dependent upon organization and connectivity. Disruptions during the transition from preplate to cortical plate can lead to significant malformation and disruption in function of the thalamus, inhibitory neuron activity, and maturation of cortical response. Injuries during the second trimester of human development have been associated with disorders such as cerebral palsy and epilepsy. [4]

The cortical plate is the final plate formed in corticogenesis. It includes cortical layers two through six. [1]

The subplate is located beneath the cortical plate. It is named for both its location relative to the cortical plate and for the time frame in which it is created. While the cortical plate matures, the cells located in the subplate establish connections with neurons that have not yet moved to their destination layer within the cortical plate.

Pioneer cells are also present in the subplate and work to create neuronal synapses within the plate. [1] In early development, synaptic connections and circuits continue to proliferate at an exponential rate.

Cortical zones

In humans the intermediate zone is located between the ventricular zone and the cortical plate. The intermediate zone contains bipolar cells and multipolar cells. The multipolar cells have a special type of migration known as multipolar migration, they do not resemble the cells migrating by locomotion or somal translocation. Instead these multipolar cells express neuronal markers and extend multiple thin processes in various directions independently of the radial glial fibers. [5] [1] This zone is only present during corticogenesis and eventually transforms into adult white matter.

The ventricular and subventricular zones exist inferior to the intermediate zone and communicate with other zones through cell signalling. These zones additionally create neurons destined to migrate to other areas in the cortex. [1] [6]

The marginal zone, along with the cortical zone, make up the 6 layers that form the cortex. This zone is the predecessor for layer I of the cortex. Astrocytes form an outer limiting membrane to interact with the pia. In humans it has been found that the cells here also form a subpial layer. [1] Cajal-Retzius cells are also present in this zone and release reelin along the radial axis, a key signaling molecule in neuronal migration during corticogenesis. [7]

Formation of layers

The cerebral cortex is divided into layers. Each layer is formed by radial glial cells located in the ventricular zone or subventricular zone, and then migrate to their final destination. [8]

Layers of the cerebral cortex, oriented from most superficial (top of image) to deepest (bottom of image). Corteza cerebral.jpg
Layers of the cerebral cortex, oriented from most superficial (top of image) to deepest (bottom of image).

Layer I

Layer I, the molecular layer, is the first cortical layer produced during neurogenesis at mice at embryonal days 10.5 to 12.5 (E10.5 to E12.5). [7] Of the six layers found within the neocortex, layer I is the most superficial and is composed of Cajal–Retzius cells and pyramidal cells. [8] This layer is unique in the aspect that these cells migrate to the outer edge of the cortex opposed to the migration experienced by the other 5 layers. Layer I is also characterized by expression of reelin, transcription factor T-box brain 1, and cortical migratory neuronal marker. [1]

Layers II and III

The second and third layers, or the external granular layer and external pyramidal layer respectively, are formed around mouse embryonal ages 13.5 to 16 days (E13.5 to E16). These layers are the last to form during corticogenesis and include pyramidal neurons, astrocytes, Stellates, and radial glial cells.

In humans the pyramidal and stellate neurons express SATB2 and CUX1. SATB2 and CUX1 are DNA binding proteins involved in determining the fate of cortical cells. [8]

Layers IV, V, and VI

The fourth, fifth and sixth layers, or the internal granular layer, internal pyramidal layer, and multiform layer, respectively, are formed during mouse E11.5 to E14.5. Included in these layers are stellates, radial glia, and pyramidal neurons. Layer VI is adjacent to the ventricular zone. During the production of these layers, transcription factors TBR1 and OTX1 are expressed along with CTIP2, or corticoneuronal zinc finger protein. [8]

Neuronal migration

Neuronal migration plays significant role in corticogenesis. Throughout the process of creating the six cortical layers, all the neurons and cells migrate from the ventricular zone, through the subplate, and come to rest at their appropriate layer of the cortex. Neuronal migration is generally subdivided into radial migration, tangential migration and multipolar migration. [1] The migration of subcortical brain functions to the cortex is known as corticalization. [9]

Cell signaling

Appropriate formation of the cerebral cortex relies heavily on a densely intertwined network of multiple signaling pathways and distinct signaling molecules. While the majority of the process remains to be understood, some signals and pathways have been carefully unraveled in an effort to gain full knowledge of the mechanisms that control corticogenesis.

Reelin-DAB1 pathway

The Reelin-DAB1 pathway is a well-defined pathway involved in corticogenesis. [10] Cajal-Retzius cells located in the marginal zone secrete reelin to start the cascade. Reelin is able to interact with specific neurons in the cortical plate and direct these neurons to their proper locations. It is thought that the result downstream from this signalling could influence the cytoskeleton. Reelin is secreted only by the Cajal-Retzius cells located in the marginal zone, and its receptors are confined to the cortical plate. This segregation could be used to understand the actions of Reelin. [1]

DAB1 is a regulator protein downstream of the reelin receptors. This protein is located inside cells residing in the ventricular zone, displaying highest concentrations in migrating pyramidal cells. When either reelin or DAB1 are inactivated in mice, the resulting phenotypes are the same. In this case, the neurons are unable to migrate properly through the cortical plate. It does not affect the proliferation of neurons and in the wild does not seem to have detrimental effects on memory or learning. [1] [6]

Sonic hedgehog

Knocking out the Sonic hedgehog, or Shh, has been shown to severely affect corticogenesis in the genetically modified mice. The ventral and dorsal sides of the cerebrum are affected as Shh expresses the transcription factors to Nkx2 which is important in patterning the cortex. Shh is also important to corticogenesis as it affects cell proliferation and differentiation, helping neuronal progenitor cells in fate determination. [11]

Bmp-7

In mice, bone morphogenetic protein 7 (Bmp-7), is an important regulator in corticogenesis, though it is not understood whether it promotes or inhibits neurogenesis. Bmp-7 can be detected in the ventricular zone and is secreted into cerebrospinal fluid (CSF). The CSF is an area to promote neurogenesis and it is believed that the synergy between Bmp-7 and other regulators promote cell division along with homeostasis. [12]

Other bone morphogenetic proteins are also known to impact corticogenesis in the mouse. Bmp2, 4, 5, and 6 are expressed during the process and can compensate for one another. For example, if Bmp-4 was absent from corticogenesis, very little would change in the cortex phenotype, due to the other Bmps helping accomplish the tasks of Bmp-4. However, Bmp-7 is the only Bmp that promotes radial glia survival and therefore considered more important. [12]

Cdk5-p35 pathway

Cdk5 has a pathway parallel to the Reelin-DAB1. This pathway affects the neuronal positioning, and results in similar malformations when absent as the Reelin or DAB1 malformations except that migration is affected at an earlier stage on the cortical plate. Cdk5/p35 pathway is also responsible for actin and microtubule dynamics involved in neuronal migration. [1]

Cyclin-dependent kinase inhibitor 1C, or p57, also affects corticogenesis. It has been shown the p57 induces cells to exit from the cell cycle and begin differentiation, but it is dependent on Cdks. p57 is able to induce neuronal progenitor cells to start differentiating into highly specialized neurons in the cortex. However, the mechanism by which p57 is able to affect such control is not yet known. [13]

Other signals

Besides the ones listed above, there are several more signals that affect corticogenesis. Cnr1 is a G protein-coupled receptor that is widely expressed throughout the brain and in interneurons. In knockout mice, the cortex exhibited decreased immunoreactivity. Nrp1, Robo1, and Robo2 have also been shown to be present and important in the development of interneurons. Cdh8 is known to be expressed in the intermediate and subventricular zone, though not in specific neurons in that area, and it is suggested to regulate fiber releasing. [6]

Disorders of cortical development

Lissencephaly

Lissencephaly, or 'smooth brain', is a disorder in which the brain does not properly form the gyri and sulci as a result from neuronal migration and cortical folding. This disorder can also result in epilepsy and cognitive impairment. [14] Type 1 lissencephaly is due to an error in migration. LIS1, also known as PAFAH1B, is a gene that is expressed in both dividing and migrating cells found in the brain. When LIS1 is deleted, lissencephaly occurs. [1]

LIS1 is thought to have several important roles in the creation of the cortex. Since LIS1 is similar to the nuclear distribution protein F (nudF), they are thought to work similarly. The nud family is known to be a factor in nuclear translocation, or moving the nuclei of daughter cells after cell division has occurred. [14] By relation, it is thought that LIS1 is a factor in neuronal migration. LIS1 is also considered to be a factor in controlling dynein, a motor protein that affects intercellular movement such as protein sorting and the process of cell division. [1]

Another protein that contributes to a lissencephaly disorder is DCX, or Doublecortin. DCX is a microtubule associated protein that is responsible for double cortex malformations. [1] DCX is found in the second layer of the cortex, and in fact is still present in immature neurons of an adult cortex. [15] It is thought that DCX affects neuronal migration through affecting the microtubule dynamics. Since DCX malformations results as a similar phenotype as with LIS1 malformations, it is thought they interact with one another on a cellular level. However, it is not yet known how this occurs. [1]

Tsc1 knockout

TSC, or tuberous sclerosis, is an autosomal dominant disorder that results in formation of tumors along neuroectodermally-derived tissue. TSC1 or TSC2 inactivation can cause TSC and the associated tumors in the brain. When inactivation of TSC1 is present during corticogenesis, malformations of cortical tubers, or abnormal benign tissue growth, along with white matter nodes would form in mice. This replicates the effect TSC is found to have in humans afflicted with TSC. In the mice there would be a lack of GFAP in astrocytes however astrogliosis would not occur like in the human TSC. [16]

Human cortex malformation (overfolding)

Variations within the sodium channel SCN3A, and Na+/K+,ATPase (ATP1A3), has been implicated in cortical malformations. [17] [18]

Recapitulation

Recapitulation of corticogenesis in both human and mouse embryos has been accomplished with a three dimensional culture using embryonic stem cells (ESC). By carefully using embryo body intermediates and cultured in a serum free environment cortical progenitors form in a space and time related pattern similar to in vivo corticogenesis. Using immunocytochemical analysis on mouse neural stem cells derived from ESCs, after 6 days there was evidence of neuronal differentiation. [8] The recapitulation ability only follows after the knowledge of spatial and temporal patterns have been identified, along with giving the knowledge that corticogenesis can occur without input from the brain. [19]

Related Research Articles

<span class="mw-page-title-main">Cerebral cortex</span> Outer layer of the cerebrum of the mammalian brain

The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consisting of allocortex. It is separated into two cortices, by the longitudinal fissure that divides the cerebrum into the left and right cerebral hemispheres. The two hemispheres are joined beneath the cortex by the corpus callosum. The cerebral cortex is the largest site of neural integration in the central nervous system. It plays a key role in attention, perception, awareness, thought, memory, language, and consciousness. The cerebral cortex is part of the brain responsible for cognition.

<span class="mw-page-title-main">Reelin</span> Large secreted extracellular matrix glycoprotein involved in neuronal migration

Reelin, encoded by the RELN gene, is a large secreted extracellular matrix glycoprotein that helps regulate processes of neuronal migration and positioning in the developing brain by controlling cell–cell interactions. Besides this important role in early development, reelin continues to work in the adult brain. It modulates synaptic plasticity by enhancing the induction and maintenance of long-term potentiation. It also stimulates dendrite and dendritic spine development and regulates the continuing migration of neuroblasts generated in adult neurogenesis sites like the subventricular and subgranular zones. It is found not only in the brain but also in the liver, thyroid gland, adrenal gland, Fallopian tube, breast and in comparatively lower levels across a range of anatomical regions.

The development of the nervous system, or neural development (neurodevelopment), refers to the processes that generate, shape, and reshape the nervous system of animals, from the earliest stages of embryonic development to adulthood. The field of neural development draws on both neuroscience and developmental biology to describe and provide insight into the cellular and molecular mechanisms by which complex nervous systems develop, from nematodes and fruit flies to mammals.

<span class="mw-page-title-main">Lissencephaly</span> Medical condition

Lissencephaly is a set of rare brain disorders whereby the whole or parts of the surface of the brain appear smooth. It is caused by defective neuronal migration during the 12th to 24th weeks of gestation resulting in a lack of development of brain folds (gyri) and grooves (sulci). It is a form of cephalic disorder. Terms such as agyria and pachygyria are used to describe the appearance of the surface of the brain.

Pachygyria is a congenital malformation of the cerebral hemisphere. It results in unusually thick convolutions of the cerebral cortex. Typically, children have developmental delay and seizures, the onset and severity depending on the severity of the cortical malformation. Infantile spasms are common in affected children, as is intractable epilepsy.

<span class="mw-page-title-main">DAB1</span> Protein-coding gene in the species Homo sapiens

The Disabled-1 (Dab1) gene encodes a key regulator of Reelin signaling. Reelin is a large glycoprotein secreted by neurons of the developing brain, particularly Cajal-Retzius cells. DAB1 functions downstream of Reln in a signaling pathway that controls cell positioning in the developing brain and during adult neurogenesis. It docks to the intracellular part of the Reelin very low density lipoprotein receptor (VLDLR) and apoE receptor type 2 (ApoER2) and becomes tyrosine-phosphorylated following binding of Reelin to cortical neurons. In mice, mutations of Dab1 and Reelin generate identical phenotypes. In humans, Reelin mutations are associated with brain malformations and mental retardation. In mice, Dab1 mutation results in the scrambler mouse phenotype.

A pioneer neuron is a cell that is a derivative of the preplate in the early stages of corticogenesis of the brain. Pioneer neurons settle in the marginal zone of the cortex and project to sub-cortical levels. In the rat, pioneer neurons are only present in prenatal brains. Unlike Cajal-Retzius cells, these neurons are reelin-negative.

<span class="mw-page-title-main">Reeler</span> Mouse mutant

A reeler is a mouse mutant, so named because of its characteristic "reeling" gait. This is caused by the profound underdevelopment of the mouse's cerebellum, a segment of the brain responsible for locomotion. The mutation is autosomal and recessive, and prevents the typical cerebellar folia from forming.

<span class="mw-page-title-main">VLDL receptor</span> Protein-coding gene in the species Homo sapiens

The very-low-density-lipoprotein receptor (VLDLR) is a transmembrane lipoprotein receptor of the low-density-lipoprotein (LDL) receptor family. VLDLR shows considerable homology with the members of this lineage. Discovered in 1992 by T. Yamamoto, VLDLR is widely distributed throughout the tissues of the body, including the heart, skeletal muscle, adipose tissue, and the brain, but is absent from the liver. This receptor has an important role in cholesterol uptake, metabolism of apolipoprotein E-containing triacylglycerol-rich lipoproteins, and neuronal migration in the developing brain. In humans, VLDLR is encoded by the VLDLR gene. Mutations of this gene may lead to a variety of symptoms and diseases, which include type I lissencephaly, cerebellar hypoplasia, and atherosclerosis.

<span class="mw-page-title-main">Radial glial cell</span> Bipolar-shaped progenitor cells of all neurons in the cerebral cortex and some glia

Radial glial cells, or radial glial progenitor cells (RGPs), are bipolar-shaped progenitor cells that are responsible for producing all of the neurons in the cerebral cortex. RGPs also produce certain lineages of glia, including astrocytes and oligodendrocytes. Their cell bodies (somata) reside in the embryonic ventricular zone, which lies next to the developing ventricular system.

<span class="mw-page-title-main">Low-density lipoprotein receptor-related protein 8</span> Cell surface receptor, part of the low-density lipoprotein receptor family

Low-density lipoprotein receptor-related protein 8 (LRP8), also known as apolipoprotein E receptor 2 (ApoER2), is a protein that in humans is encoded by the LRP8 gene. ApoER2 is a cell surface receptor that is part of the low-density lipoprotein receptor family. These receptors function in signal transduction and endocytosis of specific ligands. Through interactions with one of its ligands, reelin, ApoER2 plays an important role in embryonic neuronal migration and postnatal long-term potentiation. Another LDL family receptor, VLDLR, also interacts with reelin, and together these two receptors influence brain development and function. Decreased expression of ApoER2 is associated with certain neurological diseases.

The development of the nervous system in humans, or neural development or neurodevelopment involves the studies of embryology, developmental biology, and neuroscience to describe the cellular and molecular mechanisms by which the complex nervous system forms in humans, develops during prenatal development, and continues to develop postnatally.

<span class="mw-page-title-main">EMX1</span> Protein-coding gene in the species Homo sapiens

Homeobox protein EMX1 is a protein that in humans is encoded by the EMX1 gene. The transcribed EMX1 gene is a member of the EMX family of transcription factors. The EMX1 gene, along with its family members, are expressed in the developing cerebrum. EMX1 plays a role in specification of positional identity, the proliferation of neural stem cells, differentiation of layer-specific neuronal phenotypes and commitment to a neuronal or glial cell fate.

<span class="mw-page-title-main">Ganglionic eminence</span>

The ganglionic eminence (GE) is a transitory structure in the development of the nervous system that guides cell and axon migration. It is present in the embryonic and fetal stages of neural development found between the thalamus and caudate nucleus.

<span class="mw-page-title-main">TBR1</span> Protein-coding gene in Homo sapiens

T-box, brain, 1 is a transcription factor protein important in vertebrate embryo development. It is encoded by the TBR1 gene. This gene is also known by several other names: T-Brain 1, TBR-1, TES-56, and MGC141978. TBR1 is a member of the TBR1 subfamily of T-box family transcription factors, which share a common DNA-binding domain. Other members of the TBR1 subfamily include EOMES and TBX21. TBR1 is involved in the differentiation and migration of neurons and is required for normal brain development. TBR1 interacts with various genes and proteins in order to regulate cortical development, specifically within layer VI of the developing six-layered human cortex. Studies show that TBR1 may play a role in major neurological diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and autism spectrum disorder (ASD).

Scrambler is a spontaneous mouse mutant lacking a functional DAB1 gene, resulting in a phenotype resembling that seen in the reeler mouse. The strain was first described by Sweet et al. in 1996.

<span class="mw-page-title-main">Eomesodermin</span> Protein-coding gene in the species Homo sapiens

Eomesodermin also known as T-box brain protein 2 (Tbr2) is a protein that in humans is encoded by the EOMES gene.

<span class="mw-page-title-main">Glucocorticoids in hippocampal development</span> HippoCampus

The hippocampus is an area of the brain integral to learning and memory. Removal of this structure can result in the inability to form new memories as most famously demonstrated in a patient referred to as HM. The unique morphology of the hippocampus can be appreciated without the use of special stains and this distinct circuitry has helped further the understanding of neuronal signal potentiation. The following will provide an introduction to hippocampal development with particular focus on the role of glucocorticoid signaling.

Cajal–Retzius cells are a heterogeneous population of morphologically and molecularly distinct reelin-producing cell types in the marginal zone/layer I of the developmental cerebral cortex and in the immature hippocampus of different species and at different times during embryogenesis and postnatal life.

<span class="mw-page-title-main">Radial unit hypothesis</span> Conceptual theory of cerebral cortex development

The Radial Unit Hypothesis (RUH) is a conceptual theory of cerebral cortex development, first described by Pasko Rakic. The RUH states that the cerebral cortex develops during embryogenesis as an array of interacting cortical columns, or 'radial units', each of which originates from a transient stem cell layer called the ventricular zone, which contains neural stem cells known as radial glial cells.

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