Genetic Approaches to Study Neuronal Function and Dysfunction
My lab has been pursuing functional analyses of genes essential for nervous system development, with a particular focus on the mouse atonal homolog 1 (Math1). Mice lacking Math1 die shortly after birth from a failure to initiate respiration, and they lack cerebellar granule neurons, pontine neurons, hair cells in the vestibular and auditory systems, and the D1 interneurons of the spinocerebellar tracts. Math1 is also essential for the development of secretory cells in the gut (Paneth, goblet, and enteroendocrine cells), and the enteroendocrine cells secrete neuropeptides that modulate gut proprioception. That a single gene controls the genesis and/or differentiation of multiple components of the proprioceptive pathway was a surprise. Recently we discovered that Math1 also governs multiple components of the auditory and vestibular pathways, and within the cerebellum it controls the genesis of some deep cerebellar neurons in addition to granule neurons. Identification of the Math1 -dependent neurons allowed us to propose that Math1 redefines the rhombic lip and its derivatives.
Recently, we determined that TCF4's interaction with Math1 is critical for specification of pontine nucleus neurons, a finding that provides insight into the mechanisms underlying transcriptional programs that regulate neuronal differentiation. A conditional allele is allowing us to analyze Math1 's postnatal function in the proprioceptive pathway and to pinpoint the neurons involved in respiration. We are pursuing the identification of Math1 's downstream targets to define the molecular pathways involved in the differentiation of the diverse cell types dependent on Math1 . Such targets are likely to prove relevant to a variety of developmental disorders.
Relevance of the project to IDDRC mission:
Our studies of Math1's role in neurodevelopment significantly revised our understanding of cerebellar development and anatomy. It allowed us to pinpoint a significant cause of deafness, which another group was subsequently able to treat in animal models using gene therapy. Interestingly, haploinsufficiency of TCF4, a MATH1 interactor, causes Pitt-Hopkins mental retardation syndrome. Thus our functional studies of both proteins are likely to shed insight about the developmental defects underlying Pitt-Hopkins syndrome. Our most recent work on respiratory regulation promises to shed light on complex disorders of infant respiration and proprioception such as SIDS (Sudden Infant Death Syndrome).