Search

The coordination of progenitor self-renewal, neuronal production, and migration is essential to the normal development and evolution of the cerebral cortex. Numerous studies have shown that the Notch, Wnt/beta-catenin, and Neurogenin pathways contribute separately to progenitor expansion, neurogenesis, and neuronal migration, but it is unknown how these signals are coordinated. In vitro studies suggested that the mastermind-like 1 (MAML1) gene, homologue of the Drosophila mastermind, plays a role in coordinating the aforementioned signaling pathways, yet its role during cortical development remains largely unknown. Here we show that ectopic expression of dominant-negative MAML (dnMAML) causes exuberant neuronal production in the mouse cortex without disrupting neuronal migration. Comparing the transcriptional consequences of dnMAML and Neurog2 ectopic expression revealed a complex genetic network controlling the balance of progenitor expansion versus neuronal production. Manipulation of MAML and Neurog2 in cultured human cerebral stem cells exposed interactions with the same set of signaling pathways. Thus, our data suggest that evolutionary changes that affect the timing, tempo, and density of successive neuronal layers of the small lissencephalic rodent and large convoluted primate cerebral cortex depend on similar molecular mechanisms that act from the earliest developmental stages.

Human higher cognition is attributed to the evolutionary expansion and elaboration of the human cerebral cortex. However, the genetic mechanisms contributing to these developmental changes are poorly understood. We used comparative epigenetic profiling of human, rhesus macaque, and mouse corticogenesis to identify promoters and enhancers that have gained activity in humans. These gains are significantly enriched in modules of coexpressed genes in the cortex that function in neuronal proliferation, migration, and cortical-map organization. Gain-enriched modules also showed correlated gene expression patterns and similar transcription factor binding site enrichments in promoters and enhancers, suggesting that they are connected by common regulatory mechanisms. Our results reveal coordinated patterns of potential regulatory changes associated with conserved developmental processes during corticogenesis, providing insight into human cortical evolution.

Histone acetylation is considered a major epigenetic process that affects brain development and synaptic plasticity, as well as learning and memory. The transcriptional effectors and morphological changes responsible for plasticity as a result of long-term modifications to histone acetylation are not fully understood. To this end, we pharmacologically inhibited histone deacetylation using Trichostatin A in adult (6-month-old) mice and found significant increases in the levels of the acetylated histone marks H3Lys9, H3Lys14 and H4Lys12. High-resolution transcriptome analysis of diverse brain regions uncovered few differences in gene expression between treated and control animals, none of which were plasticity related. Instead, after increased histone acetylation, we detected a large number of novel transcriptionally active regions, which correspond to long non-coding RNAs (lncRNAs). We also surprisingly found no significant changes in dendritic spine plasticity in layers 1 and 2/3 of the visual cortex using long-term in vivo two-photon imaging. Our results indicate that chronic pharmacologically induced histone acetylation can be decoupled from gene expression and instead, may potentially exert a post-transcriptional effect through the differential production of lncRNAs.

In contrast to the prenatal development of the cerebral cortex, when cell production, migration, and layer formation dominate, development after birth involves more subtle processes, such as activity-dependent plasticity that includes refinement of synaptic connectivity by its stabilization and elimination. In the present study, we use RNA-seq with high spatial resolution to examine differential gene expression across layers 2/3, 4, 5, and 6 of the mouse visual cortex before the onset of the critical period of plasticity [postnatal day 5 (P5)], at its peak (P26), and at the mature stage (P180) and compare it with the prefrontal association area. We find that, although genes involved in early developmental events such as cell division, neuronal migration, and axon guidance are still prominent at P5, their expression largely terminates by P26, when synaptic plasticity and associated signaling pathways become enriched. Unexpectedly, the gene expression profile was similar in both areas at this age, suggesting that activity-dependent plasticity between visual and association cortices are subject to the same genetic constraints. Although gene expression changes follow similar paths until P26, we have identified 30 regionally enriched genes that are prominent during the critical period. At P180, we identified several hundred differentially expressed gene isoforms despite subsiding levels of gene expression differences. This result indicates that, once genetic developmental programs cease, the remaining morphogenetic processes may depend on posttranslational events.

The function and synaptic connections of neurons in the cerebral cortex are defined by their position. Cortical neurons are not generated locally, but rather originate in the proliferative centers lining the ventricle. After the last mitotic division, newborn neurons migrate between hundreds of micrometers in rodents to several thousand micrometers in humans to achieve their final areal radial and laminar destination (1,2). Despite differences in length and modality of pathways, differential gene activities, and distinct molecular cues involved in guiding each neuronal family to its proper address, the accuracy of the system is a remarkable achievement of evolution. However, when the delivery program goes awry causing neurons to be arrested in ectopic position, the consequences can be focal cortical dysplasias, heterotopias, and other structural malformations. The severity of disruption to cortical modalities depends on the location and expanse of misplaced neurons. For example, malformations in the prefrontal cortex are linked to schizophrenia, whereas malformations in language and limbic areas can cause problems of social behavior or autism spectrum disorders (3–5). Additionally, early disruption to neuronal migration resulting from genetic or environmental causes during the first trimester of human development is more likely to affect deep layer projection neurons. Dysregulation of neuronal migration during the second trimester of human development affects more upper layer neurons. A promising avenue in the quest to determine the genetic basis of schizophrenia has been in bridging the massive information provided by genome-wide association studies, examination of postmortem brain tissue, and molecular genetics approaches in animal models. One gene, among those considered to be implicated in schizophrenia based on its location in the 1q21-q22 locus, is NOS1 adaptor protein (NOS1AP). It interacts with and causes the relocation of nitric oxide synthase (NOS1) to presynaptic terminals. The increased expression of NOS1AP in postmortem tissue of individuals with schizophrenia is thought to disrupt NOS1 interactions with the N-methyl-D-aspartate receptor. Surprisingly, NOS1, the binding partner of NOS1A, is expressed in the prenatal human and rodent brain before synaptic signaling ensues (6). In this issue of Biological Psychiatry, Carrel et al. (7) show the expression of NOS1AP in the frontal lobe of developing rats and that experimentally manipulating the expression level of NOS1AP causes defects in neuronal migration. Using in utero electroporation, which permits accurate spatial and temporal loss of function or gain of function, the authors show that overexpression of NOS1AP disrupts the transition of migrating neurons from the multipolar to bipolar stage in the intermediate zone. The negative effects of excess NOS1AP on neuronal migration can be rescued experimentally by short hairpin RNA–mediated knockdown. By introducing several truncated NOS1AP mutant genes in utero, the authors were able to identify the N-terminal phosphotyrosine-binding