Larry Fromm, Ph.D.
The research in my lab focuses on the mechanisms by which innervation controls gene expression in skeletal muscle. Skeletal muscle is innervated by two distinct types of neurons: motor neurons that control movement and sensory neurons that detect length. Contact of each type of neuron with developing muscle induces formation where nerves and muscles connect of specialized structures, whose formation involves transcriptional induction in muscle of specific genes in response to nerve-derived signals. We study the mechanisms by which these genes are induced by identifying the transcription factors that facilitate responsiveness to nerve-derived signals and determining how intracellular signaling relays target these transcription factors. Understanding the signaling interactions that control formation of nerve-muscle synapses and of mechanosensory structures might suggest regenerative approaches for treating certain neuromuscular disorders and sensory neuropathies.
We generally use muscle cell culture systems to develop ideas that can subsequently be tested with mouse genetic models in vivo. With cultured muscle cells, we add extracellular signaling molecules that are equivalent to signals supplied by the nerve. Using a variety of approaches, we then examine the intracellular signaling relays that lead to changes in gene expression. The approaches that we use for examining intracellular signaling mechanisms include transcriptional reporter assays to identify critical transcriptional regulatory elements, DNA-protein binding assays to identify transcription factors that bind to these elements, biochemical approaches and antibody-based assays to study transcription factor modifications and interactions, and functional studies of potential signaling proteins using inhibition by pharmacological inhibitors or RNA interference.
These studies are providing insight into how transcription in muscle is induced by both sensory and motor neuron derived signals, including the roles for the transcription factors cAMP response element binding protein (CREB) and serum response factor (SRF) in responding to sensory neuron derived signals and how CREB and SRF are activated as part of the signaling response. We have also provided insight into the roles for the transcription factors GA-binding protein (GABP) and early growth response 1 (Egr1) in responding to motor neuron derived signals. From these various studies, potentially novel cell signaling mechanisms might be revealed.
1. Herndon, C.A., Ankenbruck, N., and Fromm, L. 2014. The Erk MAP Kinase Pathway is Activated at Muscle Spindles and is Required for Induction of the Muscle Spindle-specific Gene Egr3 by Neuregulin1. J. Neurosci. Res. 92: 174-184. PubMed; PDF
2. Herndon, C.A., Ankenbruck, N., Lester, B., Bailey, J., and Fromm, L. 2013. Neuregulin1 Signaling Targets SRF and CREB and Activates the Muscle Spindle-specific Gene Egr3 Through a Composite SRF-CREB-binding Site. Exp. Cell Res. 319: 718-730. PubMed; PDF
3. Herndon, C.A., Snell J., and Fromm, L. 2011. Chromatin modifications that support acetylcholine receptor gene activation are established during muscle cell determination and differentiation. Mol. Biol. Rep. 38: 1277-1285. PubMed; PDF