ELUCIDATION OF GENE REGULATORY NETWORK CONTROLLING EMBRYONIC SKELETAL DEVELOPMENT: FROM THE PERSPECTIVE OF PAX1 & PAX9

Abstract

Pax1 and Pax9 are critical and function redundantly in the patterning and differentiation of the sclerotomal cells that give rise to the vertebral bodies and intervertebral discs (IVD) of the axial skeleton. Using loss-of-function mouse models for Pax1 and Pax9 and genome-wide technologies (microarray and ChIP-Seq), the direct and indirect targets of Pax1 and Pax9 have been identified, for the first time, in Pax1/Pax9-specific cell types of the IVD anlagen. The redundant targets of Pax1 and Pax9 were also uncovered through the use of Pax1-/-Pax9+/- and Pax1-/-Pax9-/- knockout mutants. The results revealed their roles in regulating cell proliferation, mesenchymal condensation and collagen fibrillogenesis - processes that are essential in IVD morphogenesis. A novel link between Pax1/Pax9 and Sox5 was identified, which suggests that Pax genes may assist the Sox genes in regulating the early chondrogenic genes. The identified targets can be used for modelling the regulatory network of embryonic skeleton.