Development of the cerebral cortex

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. Subplate 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. The cortical plate is the final plate formed in corticogenesis. It includes cortical layers two through six. 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. 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. 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. ==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. 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. 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. 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. ==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. ==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. 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. 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. 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. 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. ==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. 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. 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. Human cortex malformation (overfolding) Variations within the sodium channel SCN3A, and Na+/K+,ATPase (ATP1A3), has been implicated in cortical malformations. ==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. ==References==