Snider Lab
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1. Functions of the Raf/MEK/ERK signaling pathway in nervous system development. My laboratory studies biological functions of neuronal growth factors acting via receptor tyrosine kinases (RTKs). Trophic factor binding to RTKs triggers the activity of key intracellular signaling cascades, including PI3K/Akt/GSK-3, PLCγ, and MAPK. Recent studies have shown that genetic mutations in the canonical RAF/MEK/ERK pathway and its upstream modifiers and downstream meaditors lead to human neurodevelopmental syndromes ("Rasopathies"). However, our understanding of these syndromes has been impeded by the fact that we know little about the consequences of disrupted ERK/MAPK signaling in the developing brain. Thus, we have initiated studies to define the cell-type specific functions of the ERK/MAPK pathway in the control of trophic signaling in the nervous system. We have generated a number of mouse genetic models to study the effects of altered RAF/MEK/ERK signaling on distinct glial and neuronal subtypes during development. In the peripheral nervous system, we have found that ERK/MAPK is absolutely necessary for Neuregulin/ErbB effects on Schwann cell specification and myelination (Newbern et al. Neuron. 2011. 69:91-105.) Embryonic neuronal development appears to be relatively less dependent on ERK/MAPK than glia, however, our data does show that sensory neurons require ERK/MAPK signaling for NGF-dependent cutaneous arborization. We have recently generated several new models that will allow for the study of ERK/MAPK functions in neuronal classes in the developing brain. These mouse models will allow us to define RAF/MEK/ERK functions downstream of key trophic cues in the CNS, such as FGF/FGFR, BDNF/TrkB, and NRG/ErbB4. This work will also contribute to an understanding of the mechanistic basis of neurodevelopmental defects resulting from mutations in the Raf/MEK/ERK cascade. Funding: NS 031768-17
2. Functions of the GSK-3 signaling pathway in nervous system development. Glycogen Synthase Kinase-3 (GSK-3) α and β are serine/threonine kinases that are key downstream regulators of multiple signaling pathways essential for neural development, including Wnt/β-catenin, RTK/PI3K and Shh. GSK-3 activity during development is regulated by protein implicated in schizophrenia DISC1 Prior work from our lab found that deletion of GSK-3 in the progenitors of the developing cortex drastically increases the number of neural progenitors in the cortex indicating an essential role for GSK-3 in neurogenesis (Kim WY et al. Nat Neurosci 2009. 12(11):1390-7). Several in vitro studies implicate GSK-3 as a regulator of neuronal polarity and morphogenesis - arguing for GSK-3 to be a key regulator of not only progenitor fate, but of overall cortical development. However, the functions of GSK-3 in post mitotic neurons in vivo are still unknown. We are now identifying the in vivo role of GSK-3 in post-mitotic neurons of the developing mouse neocortex and determining the signaling pathway involved in post-mitotic GSK-3 function. Tools employed include definitive mouse genetic models, in utero electroporation with postnasal survival, and time lapse imaging of cortical migration. Funding: NS 050968-07
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