Tissue-specific activities of the Fat1 cadherin cooperate to control neuromuscular morphogenesis

PLoS Biol. 2018 May 16;16(5):e2004734. doi: 10.1371/journal.pbio.2004734. eCollection 2018 May.

Abstract

Muscle 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 tissue-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 MNs. Here, we show that constitutive Fat1 disruption interferes with expansion and differentiation of the CM muscle, with its motor innervation and with specification of its associated MN pool. Fat1 is expressed in muscle progenitors, in associated mesenchymal cells, and in MN subsets, including the CM-innervating pool. We identify mesenchyme-derived connective tissue (CT) as a cell type in which Fat1 activity is required for the non-cell-autonomous control of CM muscle progenitor spreading, myogenic differentiation, motor innervation, and for motor pool specification. In parallel, Fat1 is required in MNs to promote their axonal growth and specification, indirectly influencing muscle progenitor progression. These results illustrate how Fat1 coordinates the coupling of muscular and neuronal morphogenesis by playing distinct but complementary actions in several cell types.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cadherins / physiology*
  • Connective Tissue / metabolism
  • Female
  • Glial Cell Line-Derived Neurotrophic Factor / metabolism
  • Male
  • Mesoderm / physiology
  • Mice
  • Mice, Knockout
  • Morphogenesis*
  • Motor Neurons / physiology*
  • Muscles / embryology*
  • Muscles / innervation
  • Neuromuscular Junction / embryology*
  • Pregnancy
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism

Substances

  • Cadherins
  • Gdnf protein, mouse
  • Glial Cell Line-Derived Neurotrophic Factor
  • fat1 protein, mouse
  • Receptor, Platelet-Derived Growth Factor alpha

Grant support

FSHD Global Research foundation https://fshdglobal.org/ (grant number Grant 14). Funding to FH. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. FSH Society https://www.fshsociety.org/ (grant number FSHS-82014-05). Funding to FH. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. AFM-Telethon, Association Francaise contre les Myopathies https://www.afm-telethon.fr/ (grant number 15823; 16785; 20861). Funding to FH. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Agence Nationale pour la Recherche http://www.agence-nationale-recherche.fr/investissements-d-avenir/ (grant number France-BioImaging, ANR-10-INBS-04). Imaging was performed using the PiCSL-FBI core facility (IBDM, AMU-Marseille, France) supported by the Agence Nationale de la Recherche through the ‘Investments for the Future’ program. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.