Uncoupling skeletal and connective tissue patterning: conditional deletion in cartilage progenitors reveals cell-autonomous requirements for Lmx1b in dorsal-ventral limb patterning

Abstract

SUMMARYIntegration of muscle, connective tissue and skeletal patterning during development is essential for proper functioning of the musculoskeletal system. How this integration is achieved is poorly understood. There is ample evidence suggesting that skeletal pattern is programmed autonomously, whereas muscle pattern is, for the most part, programmed non-cell-autonomously. Connective tissues depend upon both muscle and skeletal tissues for their proper survival and development. Here, we employed a novel approach to dissect the coordination of musculoskeletal patterning during mouse limb development. Using both conditional gain-and loss-of-function approaches, we selectively deleted or activated the LIM-homeodomain transcription factor Lmx1b in skeletal progenitors using a Sox9-Cre knock-in allele. As Lmx1b is both necessary and sufficient to specify dorsal pattern, this approach allowed us to investigate the effect of selectively deleting or activating Lmx1b in skeletal progenitors on muscle, connective and skeletal tissues during limb development. Our results indicate that whereas Lmx1b activity is required autonomously in skeletal progenitors to direct dorsal pattern, loss or gain of Lmx1b activity in skeletal progenitors has no effect on muscle or connective tissue patterning. Hence, we show for the first time that skeletal and connective tissue patterning can be uncoupled, indicating a degree of autonomy in the formation of the musculoskeletal system.

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

“…1B,E). Therefore, these data do indeed confirm the idea that Shh patterns limb muscles along the AP axis through lateral plate-derived mesenchyme in a non-cellautonomous manner, consistent with previous work indicating that the pattern of the musculature is established by the muscle connective tissue (Kardon et al 2003;Hasson et al 2010;Li et al 2010).…”

“…This myogenic differentiation is integrated with the process of pattern formation such that as the muscle cells differentiate and begin to form muscle bundles, they do so in the correct location and orientation (Kardon 1998;Kardon et al 2003;Li et al 2010). The AP organization of the muscles is established in response to Shh activity.…”

Musculoskeletal integration at the wrist underlies modular development of limb tendons

“…Interestingly, although the skeletal phenotypes of these mutants are significantly different, a phenotypic feature common to both mutants is the loss of all phalangeal joints (Dy et al, 2010;St-Jacques et al, 1999). The possibility that induction of the FDS digit segment is dependent on cues from the forming joint is further supported by the fact that formation of the MP joint is concurrent with the initial stages of FDS digit tendon induction (Li et al, 2010). Moreover, the bilateral symmetry of the MP joint also mirrors the bifurcated structure of the FDS digit tendons, suggesting that the cues governing joint symmetry might also regulate FDS digit tendon induction.…”

“Soft” tissue patterning: Muscles and tendons of the limb take their form

“…Overall, soft tissue patterning is a relatively unexplored territory in comparison to that of its associated skeleton. Because the two processes can be uncoupled (Hasson et al, 2010;Li et al, 2010) more research is needed to understand how these tissues are patterned and how their development is coordinated with that of the skeleton. The emergence of new tools and reagents has lead to significant progress in recent years.…”

“…Although much is known about the molecular pathways that determine patterning of the skeleton, the patterning and morphogenesis of its associated ''soft tissues,'' namely the muscles, tendons and ligaments and the interwoven connective tissues, have received much less attention. Recent work suggests that soft tissue and skeletal patterning can be uncoupled and that the two processes are to some extent autonomous (Hasson et al, 2010;Li et al, 2010). That, in addition to the large number of tendons and muscles and the complexity of their arrangement, suggests that lessons learned from patterning of the skeleton cannot be simply ascribed to those regulating that of the muscles and tendons.…”