Analysis of Limp1 function and interactions in muscle

This research project will be performed in the laboratory of Dr. Katherine L. Wilson in the Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, USA. It will focus on the functional characterization of the Lamin-interacting muscle protein 1 (Limp1), which is a novel A-type lamin binding partner. A-type lamins are major structural components of the nucleus. They interact with the inner nuclear membrane protein emerin, which in turn associates with the chromosomal protein BAF. Interestingly, A-type lamins and emerin are ubiquitously expressed throughout the human body, but are implicated in human muscle-specific diseases (e.g. Emery Dreifuss muscular dystrophy) suggesting an interaction of lamin/emerin complexes with myogenic regulatory proteins. Limp1 might be a key protein involved in muscle-specific function of these complexes and in human myopathies. Limp1 is primarily expressed in muscle, upregulated during myogenic differentiation and binds to a region of A-type lamins containing various disease-mutations. In addition, Limp1 appears to interact with emerin and BAF suggesting the formation of supramolecular Limp1/lamin/emerin/BAF complexes during myogenic differentiation. To test these important models, I plan to carry out biochemical analyses of these complexes in vitro, which will be verified in vivo using muscle cells and tissue. Furthermore, I will investigate the role of Limp1 during muscle differentiation and regeneration with the help of gain/loss-of- function studies in muscle cells and physiological analyses in rat muscle. Finally, I will use different approaches to identify novel Limp1 binding partners in muscle. These studies will help to elucidate the molecular basis of human myopathies.