The Mueller Laboratory

Research

MECHANOTRANSDUCTION AND AUDITOR PERCEPTION

Hair cells in the inner ear are mechanosensors for the perception of sound and head movements. Sound signals directly activate mechanically gated ion channels in hair cells, leading to hair cell depolarization and the release of neurotransmitters onto afferent neurons. Of all our senses, the mechanical senses are the least well understood. My laboratory uses genetic strategies to identify components of the mechanotransduction machinery of hair cells. Using ENU mutagenesis, we have generated mouse lines that are afflicted with deafness. We have cloned the affected genes and studied their function for auditory perception by a combination of histological, biochemical and electrophysiological methods. Using this strategy, we have identified several components of the mechanotransduction machinery of hair cells. Some of the identified genes have other functions in the auditory system such as in the development of hair cells and in neurotransmission. All of the identified genes are also linked to auditory impairment in humans. Current efforts are aimed at the identification of additional components of the mechanotransduction machinery of hair cells and at the mechanisms by which these proteins are regulated by mechanical force. We are also interested in the identification of genes and mechanisms important for the processing of sound signals in the CNS

NEURAL STEM CELLS AND NEOCORTICAL DEVELOPMENT

A second project analyzes the mechanisms that regulate the differentiation of neural stem cells during neocortical development, and how neurons that are derived from stem cells are integrated into neocortical circuits. We have identified subclasses of neuronal progenitor cells that generate distinct subclasses of excitatory projection neurons in the neocortex. We have also defined some of the mechanisms by which these neurons migrate into the developing neocortex. Current projects define the genetic and epigenetic mechanisms that instruct the fate of neuronal progenitors and that lead to the generation of distinct subtypes of neocortical projection neurons. We are also analyzing the molecular mechanisms that lead to the integration of these neurons into neocortical circuits. Our studies are directly relevant to understanding disease mechanisms since defects in the development of the neocortex are associated with neurological and psychiatric disorders such as schizophrenia, autism spectrum disorder and depression.