Matching motoneuron subtypes and myofiber subtypes: from embryonic development to pathogenesis – MOTOMYO

It is known that adult myofibers diversity, and more particularly their fast subtypes is finely controlled by corresponding motoneuron (MN) diversity, yet the determinants of this MN diversity and how their specific properties may finely tune myofiber phenotypes remain to be characterized. The overall goal of this project is to define the regulatory mechanisms determining the crosstalk between MN subtypes and myofiber subtypes that preside to the expression of a single myosin heavy chain (Myh) gene in the hundreds of nuclei present in a given fiber, the mechanisms controlled by MN firing involved in the control of specific signaling cascades in the myofiber, and the mechanisms presiding to the differential vulnerability of MN subtypes observed in mouse models of ALS and SMA human pathologies. Several complementary mouse mutant models will be studied allowing the characterization of the molecular mechanisms presiding the dialog between motoneuron and myofiber subtypes. The transcription factors and signaling pathways involved will be identified. The mechanisms allowing the preservation of the neuromuscular system of ALS mutant mice after specific physical exercise will be identified by snRNA-seq. By in vivo optogenetics in zebrafish we will link fast subtypes MN firing with specific muscle contraction properties and locomotor speed, power and posture. This ambitious project that brings together three collaborative teams with complementary expertise will lead to a better understanding, thanks to the genetic models developed and the technical new approaches developed by the three teams, of the mechanisms that preside the differential vulnerability of the neuromuscular apparatus subtypes observed in human physiopathology.