Development of a subset of forelimb muscles and their attachment sites requires the ulnar-mammary syndrome gene Tbx3

Abstract

In the vertebrate limb over 40 muscles are arranged in a precise pattern of attachment via muscle connective tissue and tendon to bone and provide an extensive range of motion. How the development of somite-derived muscle is coordinated with the development of lateral plate-derived muscle connective tissue, tendon and bone to assemble a functional limb musculoskeletal system is a long-standing question. Mutations in the T-box transcription factor, TBX3, have previously been identified as the genetic cause of ulnar-mammary syndrome (UMS), characterized by distinctive defects in posterior forelimb bones. Using conditional mutagenesis in mice, we now show that TBX3 has a broader role in limb musculoskeletal development. TBX3 is not only required for development of posterior forelimb bones (ulna and digits 4 and 5), but also for a subset of posterior muscles (lateral triceps and brachialis) and their bone eminence attachment sites. TBX3 specification of origin and insertion sites appears to be tightly linked with whether these particular muscles develop and may represent a newly discovered mechanism for specification of anatomical muscles. Re-examination of an individual with UMS reveals similar previously unrecognized muscle and bone eminence defects and indicates a conserved role for TBX3 in regulating musculoskeletal development.

Coordinated development of the limb musculoskeletal system: Tendon and muscle patterning and integration with the skeleton

“…New insight into this process comes from a recent study, which identified a role for the T-box transcription factor Tbx3 in the patterning of two muscles in the forelimb, along with their skeletal attachment sites (Colasanto et al, 2016). Deletion of Tbx3 in limb mesenchyme by Prx1Cre results in loss of all three bone eminences.…”

“…In the mouse limb, Tcf4 is expressed early in lateral plate mesoderm, at ~E9.5 (Colasanto et al, 2016). By E12.5, Tcf4+ MCT cells are closely associated with but distinct from Pax7+ and MyoD+ myogenic cells (Mathew et al, 2011).…”

“…Tcf4 continues to label MCT cells surrounding myofibers throughout embryogenesis, birth, and adulthood. In addition to the MCT, the aponeurosis (the tendon tissue at the muscle origin) as well as bone eminences are also derived from Tcf4-lineage cells (Colasanto et al, 2016; Mathew et al, 2011). Although it is not yet clear whether Tcf4 labels the progenitors for all eminences or only a subset of progenitors, the expression of Tcf4 at these sites points to a potential cell population that may integrate muscle, tendon, and attachment patterning during limb development.…”

“…While Tbx5 deletion disrupts patterning for all forelimb muscles, loss of Tbx3 is restricted to only two muscles (lateral triceps and brachialis) and three bone eminences (olecranon, deltoid tuberosity, and the greater tubercle), which considerably simplifies phenotypic analysis and interpretation (Colasanto et al, 2016). Similar to what was shown for Tbx5 and Tbx4, the timing of Tbx3 deletion is also very important.…”

“…However, recent findings now indicate that the secondary skeletal structures (ie. the bone eminences) depend on cues from tendon and muscle; indeed the patterning of individual muscles is tightly coordinated with their attachment sites (Blitz et al, 2013; Blitz et al, 2009; Colasanto et al, 2016). Similarly, while some features of tendon development are autonomous, key stages rely on signals emanating from muscle and cartilage, consistent with the functional role of tendon in connecting muscle to skeleton (Havis et al, 2016; Huang et al, 2015b).…”