Notochord-dependent expression of MFH1 and PAX1 cooperates to maintain theproliferation of sclerotome cells during the vertebral column development

During axial skeleton development, the notochord is essential for the induc tion of. the sclerotome and for the subsequent differentiation of cartilage forming the vertebral bodies and intervertebral discs. These functions are mainly mediated by the diffusible signaling molecule Sonic hedgehog. The p roducts of the paired-box-containing Pax1 and the mesenchyme forkhead-1 (Mf h1) genes are expressed in the developing sclerotome and are essential for the normal development of the vertebral column. Here, we demonstrate that M fh1 like Pax1 expression is dependent on Sonic hedgehog signals from the no tochord, and Mfh1 and Pax1 act synergistically to generate the vertebral co lumn. In Mfh1/Pax1 double mutants, dorsomedial structures of the vertebrae are missing, resulting in extreme spina bifida accompanied by subcutaneous myelomeningocoele, and the vertebral bodies and intervertebral discs are mi ssing. The morphological defects in Mfh1/Pax1 double mutants strongly corre late with the reduction of the mitotic rate of sclerotome cells. Thus, both the Mfh1 and the Pax1 gene products cooperate to mediate Sonic hedgehog-de pendent proliferation of sclerotome cells. (C) 1999 Academic Press.