The molecular and genetic mechanisms of neocortex development (2024)

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I. Overview of Neocortex Development

In humans, as in other vertebrates, the remarkably complex central nervous system (CNS) begins by the process of neural induction as a relatively simple collection of cells on the dorsal side of the gastrula-stage embryo, the neural plate ¹. The plate eventually expands, its lateral ends fold upwards and towards each other at the midline and fuse into the embryologic neural tube at around embryonic day (E) 30 in humans ².

In mammals, the developing neocortex forms in the dorsolateral wall at the rostral end of this neural tube. Here in the embryonic cerebral vesicles, or prosencephalon, the vast majority of neurons that are destined for the neocortex arise in a pseudostratified epithelial cell layer made up of two distinct germinal regions that surround the early ventricular lumen: the ventricular zone (VZ) located immediately adjacent to the ventricle and the subventricular zone (SVZ) which lies superficially on the VZ ³ (Fig. 1).

The early cycles of cellular proliferation in the VZ result primarily in the symmetrical expansion of cells termed radial glia (RG). These RG are direct descendants of the neural plate and as such have been shown to be pluripotent neural stem cells in nature retaining the capacity for both producing multiple neural cell types and for self-renewal ^4–6. This process determines not only the total pool of neural stem cells, or so-called proliferative units, from which the nascent cortical structure is later derived but also markedly increases both the surface area and thickness of the VZ. At around E33 a second phase of proliferation predominates, in which the stem cells begin to divide asymmetrically to produce a single clone and a more committed neural progenitor that temporarily withdraws itself from the cell cycle. [they did not respond to your note about simplifying this sentence] This process marks the beginning of neurogenesis ⁷.

The next key step in neocortical development following neural progenitor proliferation is migration which occurs between weeks 10–20 in the human ³. As mentioned earlier, the mature mammalian neocortex contains six layers of neurons. Development of these layers involves both radial and tangential migration routes that are taken by the various neuronal progenitors on their way to their final laminar destination (Fig. 1). Congenital migration disorders may display derangements in either one or both directions.

In the first stage of neural migration, the preplate forms (Fig. 1–2). It is composed of the first wave of neural progenitors migrating out of the VZ. Concurrently, Cajal-Retzius cells appear at the outermost aspect of the preplate. This specialized population of early neurons will secrete reelin, a signaling molecule that will help attract subsequent waves of migrating neural progenitors ⁸. In the next migrational stage, a second wave of post-mitotic neural progenitors enters the preplate and splits it into the more superficial marginal zone (MZ) and the subplate (SP) below constituting the embryologic cortical plate. Subsequent waves of migrating neuronal progenitors will migrate past the subplate stopping just short of the MZ (or layer I of the mature cortex) forming the various neocortical lamina in the process. Early birth-dating studies using tritiated thymidine in both primates and rodents established that these progenitors accumulate in their respective layers using a radial, inside-out sequence pattern with the earliest born neurons populating the innermost lamina (or layer VI) and subsequent waves becoming the more superficial layers V, IV, III, and II, respectively ^9,10. Another key recent observation in this field involves cortical neurons that express the neurotransmitter gamma-amino-butyric acid (GABA). These neurons appear to derive almost exclusively from the more distant germinal zones of the medial and lateral ganglionic eminences (MGE/LGE). From here they migrate tangentially to their respective laminar destination in the neocortex [they did not respond to your question, which laminae do they migrate into?] ¹¹. Recently it has also been shown that neurons destined for a specific layer of neocortex are generated closely in time whether they originate in the nearby VZ or the more distant MGE/LGE ¹².

As the development of the brain proceeds, the final process in the formation of the fully mature mammalian neocortex is the establishment of functional connections between the various brain regions. One of the more fascinating stories to have developed in recent years involves the role of transient laminar zones within the developing neocortex known as the subplate (Fig. 2), which act as “waiting rooms” where axons making their way to the cortex temporarily arrest before continuing on towards their respective targets [they did not respond to your request for references here]. The subplate is easily visible as a major structure in the fetal brain on pathology or brain MRI, but after development it is largely replaced by white matter in the adult.

II. Advances in Neocortical Neurogenesis

Much of our understanding of the generation of cell type diversity found in the mature neocortex is based on studies primarily done in both chicks and mice. In particular, the results from work done on spinal cord and retina development in these animals reveal that across the entire CNS, various compartments share common developmental strategies. One such strategy involves the specification (around the time of neural tube formation) or patterning of the early neocortical primoridia in response to extracellular (often secreted) morphogen gradients, such as sonic hedgehog (Shh), bone morphogenetic protein (Bmp) and fibroblast growth factor (Fgf) ^13–15. A number of transcription factors genes, most notably of the homeodomain and basic helix-loop-helix (bHLH) class, are resultantly expressed and inform their respective progenitor “pools” to commit to a particular cellular fate ^16,17. This process has been deemed the transcriptional factor “combinatorial code”. It allows an exponential number of cellular fates to be generated by a relatively modest amount of transcription factor gene products. For example, in theory, a code based on only two homeodomain and three bHLH genes can result in as many as 25 different specific neocortical cell types.

Besides the laminar organization that the developing neocortex takes on, the mature neocortex also subdivides in a tangential fashion. Two main mechanisms appear to take hold of the development of the neocortex along this axis. The first follows, as just mentioned, that the tangential subdivisions of the early neocortex are prespecified into a sort of “protomap” by gradients and counter-gradients of molecules during neurogenesis ^18–20. The second mechanism or “protocortex hypothesis” holds that a particular neuron’s fate is determined by its attachment to thalamocortical afferents that made their way into the developing neocortex ^21,22. Recent molecular evidence strongly supports both of these mechanisms as fundamental in establishing the final elements of mature neocortical differentiation and functional connectivity.

Primary microcephaly (MCPH) is the clinical finding of a reduced frontal-occipital head circumference (FOC) of greater than 3 standard deviations below age and sex-matched controls, reflecting a reduced brain volume ²³, in the absence of other causes or physical finding. It has been hypothesized that the reduced size of the brain in MCPH patients is due to premature asymmetric division of neural stem cells in proliferative zones such as the VZ resulting in a reduced number of post-mitotic neural progenitors. Microcephalic individuals generally have a small cerebral cortex and hence the majority are mentally retarded. MCPH in particular is typically an autosomal recessive disorder resulting directly from hypoplasia of the cerebral cortex with a generalized reduction in the overall size of the brain, OFCs [do you know what this stands for?] are typically 4 to 12 standard deviations below normal, and patients have mild-to-severe mental retardation as a result. Surprisingly these patients tend to lack any other predominant neurologic features such as spasticity or epilepsy.

MCPH is genetically heterogeneous, mapping thus far to six known loci, four of which have been identified ²⁴. Immunofluorescence studies reveal that they encode proteins that localize to the cellular centrosome, suggesting a mitotic yet brain-specific mechanism responsible for limiting the number of neural progenitors produced. Further insights into the role of MCPH gene products will no doubt be of therapeutic significance in the future, in particular towards identifying and/or establishing clinically beneficial neural stem cell lines for transplant.

III. Advances in Neural Migration

Despite the similarity with spinal cord and retina, there exists an important added complexity with respect to the generation of the cell diversity found within the mature neocortex. There exists two broad classes of neocortical neurons: interneurons that express the neurotransmitter GABA and make relatively local connections, and projection neurons that express glutamate and extend axons to both local intracortical and distant subcortical and subcerebral targets. During development, projection neurons are generated primarily in the dorsolateral (or pallial) wall of the telencephalon in the germinal VZ and SVZ zones we previously mentioned ²⁵. From there they will migrate relatively locally in a radial inside-out fashion to their respective lamina. This development is in contrast to that of GABA-containing interneurons which are generated in the ganglionic eminences of the ventral (or subpallial) telencephalon and migrate relatively long distances to their final neocortical destination.

Compelling evidence is accumulating that demonstrates these cells find their final destination within the developing neocortex specifically through a rearrangement of cytoskeletal components in response to extracellular cues mediated by various intracellular signaling pathways ²⁶. Thought of in this way, three large classes of genes underlie the vast majority of neural migration disorders that are seen clinically: those involving the formation of the extracellular environment encountered by migrating neurons and axons, those encoding for intracellular signaling mechanisms, and finally those encoding the intracellular machinery that mediates cellular and axonal physical movement ²⁷. One such family of genes involved in extracellular environment encodes for the enzymatic regulators of glycosylation, which in turn control the appearance of a specific extracellular cue that is encountered by migrating cells. Mutations in this group appear to delineate boundaries along a particular pathway where a cell may arrest during migration. An example in humans is the genes involved in the brain phenotype known as cobblestone lissencephaly (CL), in which the surface of the brain has a disorganized bumpy exterior lacking both gyri and sulci. Microscopically, however, these bumps consist of collections of neurons that abnormally migrated past the pial layers and on into the meninges. In some instances, the abnormally migrating neurons have been thought of as having crossed from one side of the cerebral hemisphere to the other, fusing the two together at the midline [they did not respond to your note that this was not clear]. CL, however, is only one feature in a group of conditions known as the congenital muscular dystrophies (CMD). These disorders, which are characterized by the features of muscular dystrophy, developmental eye abnormalities and CL, include f*ckuyama congenital myotonic dystrophy (FCMD), muscle eye-brain disorder (MEB) and Walker-Warburg syndrome (WWS). Recent work involving the genetic background of these disorders reveals that the mutated genes in this group encode actual or putative glycosyltransferases that detrimentally affect the dystrophin-glycoprotein complex ^28–31. CL itself appears to be the result of either loss of the integrity of the limiting glial membrane, the “stop signal” found there, or the dissociation of migrating neurons from the otherwise intact migrational scaffold.

IV. Advances in Neural Connectivity

When neurons near their final laminar destination, they will both send and receive axons and form dendrites and synapses with both local and distant cerebral structures. This process begins in the second half of gestation and extends into the postnatal period. An interesting feature is the role of transient layers of cells from the earliest migrations that seem to behave as a “waiting room” for the axons of distant afferents making their way into the neocortex. One example of these layers is the subplate (SP) that forms when the early preplate is split by a second wave of early neocortical progenitors.

When the SP was initially characterized, first described in the human and then in the monkey in mid-1970s, very few prominent neuroscientists recognized the significance of its very existence ^32–34. This fact is not surprising, however, given that the earliest reports essentially argued for a re-interpretation of neocortical laminar development. Another reason for missing the significance of the SP had to do with its seemingly underdeveloped state and relatively small size in experimental rodents in comparison with humans and monkeys, where it had initially been characterized ³⁵. It was not until 1991 that Rakic first demonstrated in rhesus monkey that thalamocortical axons destined for the visual cortex in fact wait in the SP just before migrating into and past the cortical plate ³⁶. Work by Shatz and her colleagues provided conclusive evidence of the SP’s role in establishing not only functional thalamocortical connections but development of the neocortex’s functional columnar architecture ^37,38. While a number of genes are known to be expressed in SP neurons, there has as yet been no evidence for specific genetic derangements leading to either absence or prolonged existence of SP.

The SP is present in all mammals but its morphological characteristics and persistence in adulthood varies among species. In the human the SP exists during the period from 13 weeks post-fertilization through 6–9 months postnatal. In fact, SP neurons and the afferent synaptic connections that meet them essentially represent the most significant reservoir of functional connectivity in the preterm infant. Thought of in this way, the SP exists at a time when neocortical synaptic architecture is still relatively immature or even absent, and more importantly coincides with the age of peak vulnerability to perinatal brain injury ^39,40. Blindness due to the impairment of visual cortex formation (“cortical blindness”) is particularly common in infants with perinatal white matter injury. Much of this association may be directly attributed to the vulnerability of the subplate and its relative importance to the development of normal visual cortex ⁴¹. Some encouraging results in the field of neuroimaging demonstrate that thalamocortical fibers residing in the SP and designated for somatosensory cortex may in fact detour around a particular lesion ⁴².

V. Looking into the future

The study of human Fragile X Syndrome (FXS) provides a hopeful glimpse into the possibility not only of better treatment but ultimately of prevention of the most common type of congenital mental retardation and autism. In humans, FXS is caused by transcriptional silencing of the Fmr1 gene that normally encodes the FX mental retardation protein (FMRP). This silencing is specifically caused by an expansion of a ‘CGG’ repeat sequence in the Fmr1 promoter region that disrupts the formation of a functional RNA polymerase complex. FMRP normally regulates the translation of mRNAs by inhibitory binding. One way FMRP accomplishes this binding is by inhibiting translation of certain proteins at the synapse ⁴³. The resultant effect is increased dendritic arborization leading to hyperconnectivity or the retainment of too many functional synapses ⁴⁴.

In addition, the protein metabotropic glutamate receptor 5 (mGluR5) appears to be involved in local protein synthesis at the synapse in response to glutaminergic activity. In particular, it appears to establish a “lasting effect” as seen in a model for long-term depression, which may in part play into its role in the impaired brain activity seen in FXS patients ^45–47. Taken together, these findings have led to the ‘mGluR theory’ of FXS. A particularly exciting prospect of this theory has been the development of potentially disease-modifying agents acting through mGluR5 ^48–50. Human trials of mGluR5 antagonists have begun for both FXS and a broad range of other neuropsychiatric conditions.

A causal connection has also been established concerning neuronal migration during development and altered neocortical excitability. The brains of individuals presenting with pharmacologically intractable epilepsy frequently contain foci of abnormally migrated neurons. Until the development of more effective anti-epileptic medications, surgical resection may be the best alternative for reducing the number of seizures in refractory cases. For those individuals whose defects are more widespread, the risks of surgery actually offer a worse prognosis. In subcortical band heterotopia (SBH) a strip of heterotopic gray matter largely composed of abnormally migrated neurons can be found between the ventricular wall and the cortical mantle separated by a band of white matter. SBH is most often caused in females by mutations in the X-linked gene doublecortin (DCX), a microtubule-binding protein found to be essential for normal migration. A rat model for SBH showed that delayed expression of Dcx rescued [they did not respond to your note “this is confusing”] the formation of SBH while also reducing seizure risk ⁵¹.

VI. Discussion/Conclusion

Congenital brain malformations are a significant cause of morbidity and mortality. In recent years, significant advances in basic neuroscience research have improved our understanding of neocortical development, both its molecular and genetic underpinnings. Continued advances in genomics and proteomics research will no doubt move us towards an even better understanding of these and other developmental processes, with the hope of one day being able to provide both parents and clinicians with the information they so desperately need to make informed decisions. Of course, to say that a leap from these basic laboratory studies into the clinical realm will occur in the next few years is probably naïve at best. Instead, we hope to convey that while the basic mechanisms of neocortical development continue to be worked out, along with the proper technical hurdles being overcome, we will no doubt begin to enter a new age of research, diagnosis, and treatment of congenital brain malformations and their associated disorders.

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