The long standing objective of research in this laboratory is to understand the cellular events and molecular mechanisms that govern development of the mammalian central nervous system. One line of investigation focuses on the fundamental issue of the regulation of cell proliferation and death (apoptosis) that determine the number of neurons allocated to the building of the cerebral cortex. The other series of studies concern molecular mechanisms involved in neuronal migration including cell-cell recognition, neuron glia-interaction and nuclear translocation.
Cortical Neuron Migration
Three-dimensional reconstruction of the relationship between migrating neuron and radial glial cell shaft, based initially on electron micrographs of serial sections of the monkey fetal cerebral wall (Rakic, 1972) has been animated (Rakic/Breunig model) and can be seen by clicking at any place on the figure. New methods are now used in the Rakic lab to study the molecular mechanisms underlying neuronal migration (e.g. Sarkisian et al. Neuron, 2007).
The most recent in vitro and in vivo studies, show how specific genes encoding signaling and morphoregulatory molecules and receptors cooperate in orchestrating multistage cellular events that include control of mode of neuronal proliferation, phenotype determination, establishment of polarity, detachment from the local substrate and migration of neurons to the proper regions of the cortex. We have proposed the models of the cascade of multiple molecular pathways and cell-cell interactions that are involved in normal and abnormal neuronal migration that underlie major disorders of higher brain function. A three-dimensional model of the basic developmental events and cell-cell interactions during corticogenesis, before formation of the final pattern of cortical synaptic connections is based on labeling DNA relocation with 3H-thymidine in a series of developing macaque monkey embryos.
The model based on Rakic, 1988 (Science, 241:170) emphasizes the radial mode of migration which underlies prominent columnar organization in primates. The cohorts of neurons generated in the ventricular zone (VZ) traverse the intermediate (IZ) and subplate zones (SP) containing "waiting" afferents from several sources (CC, TR, MB, MA) and finally pass through the earlier generated deep layers before settling in at the interface between cortical plate (CP) and marginal zone (MZ). The positional information of the neurons in the VZ and corresponding protomap within the SP and CP is preserved during cortical expansion by transient radial glial scaffolding.
We also study the effects of various epigenetic factors on the development of structural, molecular and functional cell phenotypes, and their segregation into topographic maps and synaptic neurotransmitters/receptors architecture in laminated structures (neocortex, cerebellum, hippocampus). Other research concerns analysis of normal and experimentally altered development of the visual system in developing primates. Finally, knowledge derived from genes identified in invertebrates and from genetically engineered mice are applied to developmental issues of primate neurobiology in order to achieve a greater understanding of the evolutionary growth of the cerebral cortex as well as pathogenesis of a host of genetic and acquired cellular abnormalities of this structure in humans.