Roles of engrailed proteins in granule cells during cerebellum development

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DESCRIPTION (provided by applicant): The cerebellum is a posterior brain structure located above the hindbrain that coordinates motor and cognitive function. In this proposal, I aim to determine the cellular and molecular mechanism responsible for the cerebellar hypoplasia that results from removal of the engrailed (EN) homeobox transcription factors EN1 and EN2 (refered to together as EN1/2) from granule cell progenitors (GCPs) in the external germinal layer (EGL) of the developing cerebellum (Cb). Since major cytoarchitectural defects are not detected in these mutants, there must be cell non-autonomous homeostatic scaling of other cell types to compensate for the reduced granule neuron population generated. Specification of cell types in appropriate number and position within an organ represents a key challenge in development of biological systems, both for the intrinsic function of that organ and with regards to operation of that organ within the whole organism. In neural systems, changes in the population size of neuron subtypes can affect specification or survival of post- and presynaptic neurons, an effect first demonstrated by the now classic neurotrophic hypothesis discovered by Viktor Hamburger and Rita Levi-Montalcini. The importance of size regulation in neural development is particularly emphasized by the observation of changes in brain subregion size in numerous diseases, such as microcephaly, schizophrenia and autism spectrum disorder. The proposed study involves two major aims: 1) determine the cellular processes regulated by EN1/2 in GCPs of the Cb and the responsiveness of EN1/2 mutant GCPs to the major mitogen Sonic Hedgehog (SHH); and 2) identify EN2 direct DNA binding sequences and associated genes regulated by EN1/2 that are downstream effectors of EN1/2 regulated GCP behaviors in the developing Cb.