Msx2 is a repressor of chondrogenic differentiation in migratory cranial neural crest cells†

Abstract

During early mouse embryogenesis, cranial neural crest cells (CNCC) emigrate from the posterior midbrain and rhombomeres 1 and 2 of the anterior hindbrain into the first branchial arch-derived maxillary and mandibular processes and there provide cell lineages for several phenotypes, including cartilage, bone, and tooth. Here, we report that Sox9 and Msx2 were coexpressed in a subpopulation of CNCC during their migration. Because Sox9 is a transactivator of chondrogenesis, and Msx genes can act as transcriptional repressors, we hypothesized that Sox9 expression indicates the determination of CNCC-derived chondrogenic cell lineage and that Msx2 represses chondrogenic differentiation until CNCC migration is completed within the mandibular processes. To test whether Msx2 represses chondrogenesis, we designed experiments to inhibit Msx2 function in migratory CNCC in primary cultures through the expression of loss-of-function Msx2 mutants. We showed that infection of migratory CNCC with adenovirus Msx2 mutants accelerated the rate and extent of chondrogenesis, as indicated by the expression level of type II collagen and aggrecan, and the amount of alcian blue staining. Adenovirus infections did not apparently interfere with CNCC proliferation or migration. These findings suggest that an important early event in craniofacial morphogenesis is a transient expression of both Sox9 and Msx2 during emigration into the forming mandibular processes followed by restricted expression of Sox9 within CNCCderived chondroprogenitor cells. We conclude that Msx2 serves as a repressor of chondrogenic differentiation during CNCC migration.

A pair of Sox: distinct and overlapping functions of zebrafish sox9 co-orthologs in craniofacial and pectoral fin development

“…In mammals, Bmp2, Msx2, Sox9, Col2a1, Runx2 and Col1a1 interact in the developmental pathway leading from neural crest to cartilage and bone (Healy et al, 1999;Mori-Akiyama et al, 2003;Takahashi et al, 2001). Zebrafish has duplicate copies of these six genes (Chiang et al, 2001;Ekker et al, 1997;Fisher et al, 2003;Flores et al, 2004;Martinez-Barbera et al, 1997;Postlethwait, 2004;Yan, et al, 1995;Yan et al, 2002), and we have begun to investigate their regulatory interactions to test the parallel and network models for the evolution of developmental pathways after genome duplication.…”

TWIST Family of Basic Helix-Loop-Helix Transcription Factors Mediate Human Mesenchymal Stem Cell Growth and Commitment

“…Genetic hybrid knockout studies of murine Twist-1/Msx2 heterozygotes showed that these animals displayed enhanced differentiation and proliferation of the frontal bone skeletogenic mesenchyme [53] where Msx2 is known to be highly expressed by proliferating osteogenic cells [54]. In addition, this transcription factor has been shown to be both an inhibitor and promoter of osteoblast differentiation [53,[55][56][57], and has been reported to inhibit chondrogenesis by acting as a repressor of Sox9 [58]. Collectively, these data suggest that Twist-1 and Dermo-1 may act to regulate critical transcription factors and osteo/ chongrogenic inductive factors that are important in the early events for determining cell fate decisions in human MSC populations.…”

Developmentally Regulated Expression of Msx1, Msx2 and Fgfs in the Developing Mouse Cranial Base

“…In skeletogenesis, Msx2 is an inhibitor of chondrogenesis and is involved in controlling bone morphogenesis. 27 In developing long bones, Msx2 is present in the resting and proliferative chondrocytes of the growth plate and auricular cartilage, perichondria, and osteoblasts. 20 Unexpectedly, the Msx gene expression did not seem to have an eminent role in cranial base development.…”