Radial glial cells play a critical role in the construction of the mammalian brain, initially, by providing a permissive and instructive scaffold for neuronal migration and eventually, by contributing to the formation of diverse glial cell lineages in the mature brain. Abnormalities in radial glial development, differentiation, and neuron-radial glial interactions lead to aberrant placement and connectivity of neurons and disordered lamination in human brain, an underlying cause of many congenital brain disorders such as developmental dyslexia, epilepsy, microencephaly (small brain), schizencephaly (split brain hemispheres), lissencephaly (smooth cerebrum, without convolutions), macrogyria (large convolutions), polymacrogyria (small cerebral convolutions), and tuberous sclerosis.
The aim of this proposal is to elucidate the mechanisms that determine how radial glial cells are established and maintained during embryonic cortical development and transformed into astrocytes once the generation and migration of cortical neurons are completed. To examine the molecular signals regulating this process, we have focused on glial growth factor (GGF) and its receptors (erbB2, 3, and 4). Our earlier findings demonstrate that GGF and their receptors play a crucial role in radial glial cell function in the developing cerebral cortex. GGF expressed by developing cortical neurons promotes neuronal migration on radial glia by promoting its maintenance and its function as substrate for neuronal migration and differentiation. In the absence of GGF signaling via erbB2 receptors, radial glial development is abnormal. Based on these preliminary results we hypothesize that the GGF-erbB signaling system is a crucial modulator of radial glial cell development. The proposed studies will test this hypothesis by analyzing (1) the role of GGF and its receptors, erbB2, erbB3, and erbB4, in the establishment, maintenance and transformation of radial glial cells and (2) whether developmental changes in GGF-erbB2 signaling system trigger the transformation of radial glial cells into astrocytes. Together, these studies on radial glial development and differentiation will help in deciphering the basic mechanisms guiding normal cerebral cortical development and in unveiling the pathogenesis of various developmental brain disorders where abnormal radial glial development and differentiation results in defective cerebral cortical organization.
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