Identification of the interactome of muscular LAP proteins, Erbin, Lano, and Scribble, their involvement in the endocytic recycling at the neuromuscular synapse, and their role in myogenesis

• Applicant: Professor Dr. Said Hashemolhosseini
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 427955420

The role of LAP (leucine rich repeat and PDZ domain containing) proteins, Erbin, Lano, and Scribble, in the skeletal muscle cell lineage, especially with emphasis on the neuromuscular junction (NMJ), is mostly unknown. Our preliminary data demonstrate that LAP proteins are expressed differently in the three cell entities of the NMJ, muscle cell, nerve ending, terminal Schwann cell. First, all three LAP proteins are expressed in the myofibers and accumulated underneath the postsynaptic apparatus, with Erbin and Scribble matching perfectly with the aggregates of the nicotinic acetylcholine receptors (AChR) at the NMJ. Second, in vivo ablation of Erbin is associated with significantly smaller aggregates of AChRs at NMJs and up-regulation of Lano and Scribble. Third, the reported interaction of the Erbin PDZ domain with ErbB receptors is not important for positioning of Erbin with NMJs. Fourth, recently Scribble and Erbin were reported being involved in endocytic trafficking in the central nervous system of mice, or epithelial cells in Caenorhabditis elegans, respectively. Fifth, Scribble as a scaffold and cell-polarity protein is involved in muscle satellite cell fate decision. Erbin and Lano are also known as scaffold proteins, but whether they play a role in cell-polarity is unknown. However, Erbin and Lano transcript amount increases during muscle cell differentiation. Based on these observations, we aim to ask the following questions to better understand the role of Erbin, Lano, and Scribble in muscle cell biology: 1. How are Erbin, Lano, and Scribble involved in muscle cell biology, and formation or maintenance of the postsynaptic apparatus and what are the members of their interactome? 2. Are LAP proteins also involved in endocytic trafficking of postsynaptic apparatus proteins at the NMJ, like the AChRs? 3. Do Erbin or Lano influence muscle stem cell proliferation, like it was reported for Scribble?

• DFG Programme: Research Grants