Title

Signaling pathways that regulate the expression of Prx in mandibular mesenchyme and the roles of Prx in mandibular chondrogenesis

Date of Completion

January 2008

Keywords

Biology, Molecular

Degree

Ph.D.

Abstract

Prx1 and Prx2 are closely related members of the paired-related family of homeobox genes and are co-expressed in variety of sites including craniofacial mesenchyme. The phenotypic abnormalities in Prx1-/-; Prx2-/- knock-out mice including the shortened mandible, lack of the midline symphysis, and the absence of most of the Meckel's cartilage (MC) provided direct evidence for the roles of Prx gene products in mandibular outgrowth and formation of MC. However, little is known about the signaling pathways that regulate the restricted expression of Prx gene in the mandibular mesenchyme. Furthermore, the underlying mechanisms by which lack of Prx genes affects the development of MC are relatively unknown. Thus, the goal of our studies was to gain insight into signaling pathways that regulate the expression of Prx genes in mandibular mesenchyme and their roles in chondrogenesis by mandibular mesenchyme. ^ Using the chick embryo as a model system our observations provide evidence for the stage-dependent roles of mandibular epithelium on the expression of Prx in the mandibular mesenchyme. ^ Our studies show positive roles of epithelially derived Fibroblast Growth Factors (FGF) and Sonic Hedgehog (SHH) on the expression of Prx in the mandibular mesenchyme and suggest roles for Endothelin-1 (ET-1) derived from the mesenchyme in restricting expression of Prx2 to the medial mandibular mesenchyme. ^ Our further studies show the expression of Prx1 and Prx2 in pre-osteogenic mesenchyme and perisoteum of the mandibular bones. However, Prx were not expressed in the pre-chondrogenic mesenchyme, chondrocytes of MC and perichondrium of the main body of MC. ^ Our studies show expression of Prx1a and Prx1b, the two alternatively spliced isoforms of Prx1 prior and after mandibular skeletogenesis. Overexpression of replication-competent retrovirus carrying full length Prx1a (RCAS-Prx1a) in vivo did not affect morphogenesis of the developing mandible, formation of MC and mandibular bones. Furthermore, over-expression of RCAS-Prx1a in vitro did not affect chondrogenesis in micromass cultures derived from HH23 chick mandibular mesenchyme. These observations reveal unessential roles of Prx gene products in mandibular chondrogenesis and suggest that the absence of MC in the Prx1 -/-; Prx2-/- knock-out mice is not related to direct effects of Prx in chondrogenesis. ^