Molecular Mechanisms That Control Neuronal Positioning D

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Improper brain development can lead to neurological disorders apparent during infancy or later in life. Both genetic and environmental factors influence the many aspects of brain formation that require the correct specification, positioning, and connection of neurons. We are interested in the genetic factors that regulate neuronal placement during development, in addition to the role these genes may play in adulthood. A molecular cascade has been resolved that includes a secreted ligand, Reln, cell surface receptors, LDLR and ApoER2, and a cytoplasmic adaptor molecule, Dab1, which are required for appropriate neuronal placement during development. We have previously shown that Dab1 is tyrosine phosphorylated in response to Reln stimulation of embryonic neurons; Dab1 tyrosine phosphorylation sites are requisite for normal brain structure development. We are currently generating mice with mutations in individual phosphorylation sites to determine the consequences of a partial response to Reln. We hypothesize that each phosphorylation site may activate a discreet downstream pathway that controls different aspects of the neuronal response to Reln, by promoting protein-protein interactions between Dab1 and signaling partners. We are also engaged in the identification of molecules that interact with Dab1 in a phosphotyrosine dependent manner, by both yeast two hybrid screens and biochemical affinity purification. We have identified a number of interacting molecules that we are analyzing for physiological relevance to the Reln signaling pathway. To address the role the Reln-Dab1 signal transduction pathway plays in the adult nervous system, we have generated a conditional allele of Dab1. We plan to inactivate this allele in a subset of adult neurons, such as cerebellar Purkinje cells, to assay for neurological dysfunction that may result from postnatal loss of Dab1 function.