Genetics of shoulder girdle formation: roles of Tbx15 and aristaless-like genes

Abstract

The diverse cellular contributions to the skeletal elements of the vertebrate shoulder and pelvic girdles during embryonic development complicate the study of their patterning. Research in avian embryos has recently clarified part of the embryological basis of shoulder formation. Although dermomyotomal cells provide the progenitors of the scapular blade, local signals appear to have an essential guiding role in this process. These signals differ from those that are known to pattern the more distal appendicular skeleton. We have studied the impact of Tbx15, Gli3, Alx4 and related genes on formation of the skeletal elements of the mouse shoulder and pelvic girdles. We observed severe reduction of the scapula in double and triple mutants of these genes. Analyses of a range of complex genotypes revealed aspects of their genetic relationship, as well as functions that had been previously masked due to functional redundancy. Tbx15 and Gli3 appear to have synergistic functions in formation of the scapular blade. Scapular truncation in triple mutants of Tbx15, Alx4 and Cart1indicates essential functions for Alx4 and Cart1 in the anterior part of the scapula, as opposed to Gli3 function being linked to the posterior part. Especially in Alx4/Cart1 mutants, the expression of markers such as Pax1, Pax3 and Scleraxis is altered prior to stages when anatomical aberrations are visible in the shoulder region. This suggests a disorganization of the proximal limb bud and adjacent flank mesoderm, and is likely to reflect the disruption of a mechanism providing positional cues to guide progenitor cells to their destination in the pectoral girdle.

T-box Protein Tbx18 Interacts with the Paired Box Protein Pax3 in the Development of the Paraxial Mesoderm

“…In compound mutant embryos, the scapula blade exhibited a central hole. In addition, loss of Pax3 dose-dependently increased the severity of the scapula defect in the mutants for Tbx15 (15,25), the T-box gene most highly related to Tbx18.…”

“…Interestingly, Tbx15 has been shown to synergize with a number of other transcription factor genes, including Gli3 and aristaless-type homeobox genes (Alx4 and Cart1) in scapula development (25), arguing for a complex network of developmental regulators involved in patterning/differentiation of this bone.…”

“…Since a similar scapula phenotype has been reported for mice homozygous mutant for Tbx15 (15,25), the gene most closely related to Tbx18, we decided to test whether Pax3 shows genetic interaction with Tbx15 in scapula development as well. All combinations of compound mutants were found in the expected ratio in E14.5 embryos (n ϭ 63).…”

Thearistaless-like homeobox protein Alx3 as an etiopathogenic factor for diabetes mellitus

“…14 Overlapping functions among different members of this family are likely. [15][16][17] Therefore, it is possible that a defect in one of them may be compensated by the others, resulting in a relatively mild phenotype. In this regard, at least two other aristaless-related proteins have been associated directly or indirectly with pancreatic islet function.…”

A novel mutant allele of Ncx1: a single amino acid substitution leads to cardiac dysfunction

“…In situ hybridization on whole mounts or sections was as described previously (Kuijper et al, 2005). Probes were previously described (Van Nes et al, 2006) except for Ncx1.…”