The long term goal of this research is to elucidate the molecular and cellular mechanisms by which neuregulins and their receptors influence mammalian development. Neuregulins (NRGs) are a family of structurally related signaling molecules that interact with erbB receptor tyrosine kinases (erbB2 erbB3 and erbB4). To understand the physiological role of NRG signaling pathways in mammalian development we established erbB2 null mutant mice that die of cardiac defects before embryonic (E) day 11. To study the role of erbB2 in development after E11 we genetically rescued cardiac defects of erbB2 null mutants that survive until birth. To study the role of erbB2 in development after birth we established erbB2 conditional mutant mice via the Crelox P technology. Preliminary results showed that erbB2 plays an essential role in development of the neuromuscular junction. In addition when crossed with nestin Cre mice erbB2 floxed mice displayed a phenotype resembling human Hirshsprung's disease (HRSD). Together these mice provide an excellent model for genetic anatomical cell and molecular and biochemical studies to further understand the role of erbB2 in neural development.
Aim 1 is to determine the role of erbB2 in the development of neuromuscular junction: ErbB2 mutant mice are crossed with agrin and its receptor MuSK or erbB3 mutant mice to determine how their genetic interactions influence pre and postsynaptic development including acetylcholine receptor clustering and gene activation at synaptic sites.
Aim 2 is to investigate the regulated protein phosphorylation in erbB2 mutant mice: Signaling mechanisms underlying genetic interactions of erbB2 with agrin/MuSK and erbB3 will be elucidated with an emphasis on protein phosphorylation.
Aim 3 is to determine the role of erbB2 in the development of the enteric nervous system.
Aim 4 is to characterize the autonomic nervous system in erbB2floxed/nestinCre mutant mice. Results from this research will advance our knowledge on the development of multiple parts of the nervous system and provide insights on several human diseases.
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