Tissue-specific activities of the Fat1 cadherin cooperate to control neuromuscular morphogenesis
Authors: Helmbacher Françoise 
Published: October 2017

AbstractMuscle morphogenesis is tightly coupled with that of motor neurons (MNs). Both MNs and muscle progenitors simultaneously explore the surrounding tissues while exchanging reciprocal signals to tune their behaviors. We previously identified the Fat1 cadherin as a regulator of muscle morphogenesis, and showed that it is required in the myogenic lineage to control the polarity of progenitor migration. To expand our knowledge on how Fat1 exerts its tissue-morphogenesis regulator activity, we dissected its functions by tissu-specific genetic ablation. An emblematic example of muscle under such morphogenetic control is the cutaneous maximus (CM) muscle, a flat subcutaneous muscle in which progenitor migration is physically separated from the process of myogenic differentiation, but tightly associated with elongating axons of its partner motor neurons. Here, we show that constitutiveFat1disruption interferes with expansion and differentiation of the CM muscle, with its motor innervation and with specification of its associated MN pool.Fat1is expressed in muscle progenitors, in associated mesenchymal cells, and in MN subsets including the CM-innervating pool. We identify mesenchyme-derived connective tissue as a cell type in whichFat1activity is required for the non-cell-autonomous control of CM muscle progenitor spreading, myogenic differentiation, motor innervation, and for motor pool specification. In parallel,Fat1is required in MNs to promote their axonal growth and specification, indirectly influencing muscle progenitor progression. These results illustrate howFat1coordinates the coupling of muscular and neuronal morphogenesis by playing distinct but complementary actions in several cell types.Author summaryFat cadherins are evolutionarily conserved cell adhesion molecules playing key roles in modulating tissue morphogenesis, through the control of collective cell behavior and polarity. We previously identified the mouseFat1gene as a regulator of muscle morphogenesis. The present study explores howFat1influences neuromuscular morphogenesis in the context of development of a flat subcutaneous muscle, the cutaneous maximus muscle (CM), formed by migratory progenitors emerging from forelimb levels somites, and innervated by a pool of brachial spinal motor neurons (MNs). CM development involves the rostrocaudal planar migration of muscle progenitors and subsequent elongation of muscle fibers to form a fan-shaped muscle. We previously reported thatFat1was required in muscle progenitors to modulate their migration polarity. Here, these results were expanded by exploring the contribution ofFat1activities in two other cell types, mesenchymal cells and MNs. We show thatFat1disruption in connective tissue robustly alters CM muscle morphogenesis, affecting not only progenitor migration and myofiber expansion, but also subsequently impairing axon growth and specification of cognate MNs. In parallel,Fat1acts in MNs to modulate axonal growth and neuronal specification, modestly influencing muscle morphology. Together, these results show thatFat1coordinates the coupling between muscle and neuronal development by playing complementary functions in mesenchyme, muscles and MNs. These findings could guide research on muscle pathologies associated withFAT1alterations in humans.