Autonomous and nonautonomous roles of Hedgehog signaling in regulating limb muscle formation

Abstract

Muscle progenitor cells migrate from the lateral somites into the developing vertebrate limb, where they undergo patterning and differentiation in response to local signals. Sonic hedgehog (Shh) is a secreted molecule made in the posterior limb bud that affects patterning and development of multiple tissues, including skeletal muscles. However, the cell-autonomous and non-cell-autonomous functions of Shh during limb muscle formation have remained unclear. We found that Shh affects the pattern of limb musculature non-cell-autonomously, acting through adjacent nonmuscle mesenchyme. However, Shh plays a cell-autonomous role in maintaining cell survival in the dermomyotome and initiating early activation of the myogenic program in the ventral limb. At later stages, Shh promotes slow muscle differentiation cell-autonomously. In addition, Shh signaling is required cell-autonomously to regulate directional muscle cell migration in the distal limb. We identify neuroepithelial cell transforming gene 1 (Net1) as a downstream target and effector of Shh signaling in that context.

The developmental basis of bat wing muscle

“…Although molecular mechanisms controlling the organization of skeletal muscle in space during vertebrate development are not fully understood, signalling molecules secreted from non-myogenic mesenchyme or muscle connective tissue, as well as cell adhesion molecules localized at the cell membrane of muscle connective tissue, potentially affect the architectural pattern of muscles 21,22,30,[40][41][42][43][44][45][46][47][48] . In tongue morphogenesis, cranial neural crest-derived tongue muscle connective tissue is required for organizing occipital somite-derived tongue muscle cells 49 .…”

The transition from differentiation to growth during dermomyotome-derived myogenesis depends on temporally restricted hedgehog signaling

“…In zebrafish, different levels and durations of Shh signaling specify distinct myotomal cell types (Feng et al, 2006;Hammond et al, 2007;Ingham and McMahon, 2001;Maurya et al, 2011;Wolff et al, 2003). In the chick, Shh was found to be necessary for epaxial but not limb muscle formation (Teillet et al, 1998), yet studies in mouse propose that it induces the myogenic program in the ventral limb (Anderson et al, 2012;Hu et al, 2012;Krüger et al, 2001). In addition, Shh has been shown to regulate Myf5 expression in primary epaxial RESEARCH ARTICLE Sonic hedgehog in myotome development myoblasts (Borycki et al, 1999;Chiang et al, 1996;Gustafsson et al, 2002), although other studies do not support this finding (Teboul et al, 2003).…”

Expression analysis of Gli1 and Gli2 in different tissues and muscle-derived cells of Qinchuan cattle

“…Although the expression levels of Gli1 and Gli2 in muscle are both the lowest of the 13 tissues we investigated, many previous researches have testified that Hh signaling is crucial in muscle formation during embryonic and postnatal development of vertebrates (Flynt et al, 2007;Martin et al, 2007;Straface et al, 2009;Lobbardi et al, 2011;Hu et al, 2012). At the cellular level, the Hh signaling pathway promotes the proliferation and myogenic differentiation of myoblasts (Pola et al, 2003;Li et al, 2004;Koleva et al, 2005;Elia et al, 2007;Madhala-Levy et al, 2012).…”

“…Additionally, the repression of the Hh signaling pathway induced by cyclopamine or a small interfering RNA (siRNA) of its positive component inhibited chondrogenic differentiation (Wu et al, 2013). The Hh signaling pathway promotes myogenesis in zebrafish (Flynt et al, 2007;Lobbardi et al, 2011), Xenopus (Martin et al, 2007), mouse (Straface et al, 2009;Hu et al, 2012;Voronova et al, 2013), and chick (Elia et al, 2007).…”