EXCEED THE SPACE PROVIDED. During mammalian cerebral cortical development, neural stem cells (NSCs) give rise to successive waves of neurons and glia. We have shown that the bone morphogenetic proteins (BMPs) promote specific lineage decisions that depend on the developmental stage of NSCs. Within the early embryonic ventricular zone (VZ), BMPs initially enhance cell death but later promote neuronal lineage commitment and subsequent cellular maturation and also actively suppress the generation of radial glia and oligodendrocytes. By contrast, within the late embryonic subventricular zone (SVZ), BMPs potentiatethe elaborationof astrocytesand nowactively suppress the elaboration of neurons and also oligodendrocytes. Members of the inhibitor of differentiation(ID) family regulate neurogenic basic-helix-loop-helix (bHLH) transcription factors, and ID1 and 3 inhibit neurogenesis while simultaneously preserving the NSC fate. We have found that during both embryonic neurogenesis and gliogenesis, BMPs upregulate transcripts for ID2 and ID4 in NSCs and promote ID nuclear translocation in target progenitor species. We hypothesizethat BMP-mediated cellular and lineage effects involve ID2and ID4 because inhibition of ID2 and/or ID4 expression prevents these BMP-sanctioned positive and negative developmental effects on VZ and SVZ NSCs, and preliminary analysis of ID2-/-, ID4-/- and ID2-/-ID4-/- mice has revealed defects in neural development distinct from those seen with ID1-/-, ID3-/- and ID1-/-ID3-/-mice. The basic hypotheses underlying this proposal are: 1. BMPs orchestrate cortical developmental events by promotion of specific pathways of NSC differentiation as well as active suppression of alternate lineage fates, 2. BMPs also modulate the size of the initial VZ NSC pool and progressive stages of neuronal maturation, 3. ID2 and ID4 differentially mediate these diverse processes through changing roles within distinct progenitor species.The role of ID2 and ID4 in cortical development will be examined in vitro by defining the effects of overexpressingor ablating ID2 and/or ID4 on NSC lineage commitment and responses to the BMPs. Their roles will be examined in vivo by analyzing neural development in ID2-/-, ID4-/- and ID2-/-ID4-/-mutant mice. These studies will further our understandingof the molecular mechanisms governing the changing profiles of neural lineage elaboration during embryonic cerebralcortical neurogenesis and gliogenesis.
| Qureshi, Irfan A; Mehler, Mark F (2015) Epigenetics and therapeutic targets mediating neuroprotection. Brain Res 1628:265-272 |
| Qureshi, Irfan A; Mehler, Mark F (2014) Epigenetic mechanisms underlying the pathogenesis of neurogenetic diseases. Neurotherapeutics 11:708-20 |
| Qureshi, Irfan A; Mehler, Mark F (2014) Epigenetics of sleep and chronobiology. Curr Neurol Neurosci Rep 14:432 |
| Qureshi, Irfan A; Mehler, Mark F (2014) An evolving view of epigenetic complexity in the brain. Philos Trans R Soc Lond B Biol Sci 369: |
| Qureshi, Irfan A; Mehler, Mark F (2014) Sex, epilepsy, and epigenetics. Neurobiol Dis 72 Pt B:210-6 |
| Nguyen, Giang D; Gokhan, Solen; Molero, Aldrin E et al. (2014) The role of H1 linker histone subtypes in preserving the fidelity of elaboration of mesendodermal and neuroectodermal lineages during embryonic development. PLoS One 9:e96858 |
| Qureshi, Irfan A; Mehler, Mark F (2013) Towards a 'systems'-level understanding of the nervous system and its disorders. Trends Neurosci 36:674-84 |
| Nguyen, Giang D; Gokhan, Solen; Molero, Aldrin E et al. (2013) Selective roles of normal and mutant huntingtin in neural induction and early neurogenesis. PLoS One 8:e64368 |
| Qureshi, Irfan A; Mehler, Mark F (2013) Developing epigenetic diagnostics and therapeutics for brain disorders. Trends Mol Med 19:732-41 |
| Nguyen, Giang D; Molero, Aldrin E; Gokhan, Solen et al. (2013) Functions of huntingtin in germ layer specification and organogenesis. PLoS One 8:e72698 |
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