Notochord-Dependent Expression of MFH1 and PAX1 Cooperates to Maintain the Proliferation of Sclerotome Cells during the Vertebral Column Development

Abstract

During axial skeleton development, the notochord is essential for the induction 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 products of the paired-box-containing Pax1 and the mesenchyme forkhead-1 (Mfh1) genes are expressed in the developing sclerotome and are essential for the normal development of the vertebral column. Here, we demonstrate that Mfh1 like Pax1 expression is dependent on Sonic hedgehog signals from the notochord, and Mfh1 and Pax1 act synergistically to generate the vertebral column. 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 missing. The morphological defects in Mfh1/Pax1 double mutants strongly correlate with the reduction of the mitotic rate of sclerotome cells. Thus, both the Mfh1 and the Pax1 gene products cooperate to mediate Sonic hedgehog-dependent proliferation of sclerotome cells.

Overlapping Roles for Homeodomain-Interacting Protein Kinases Hipk1 and Hipk2 in the Mediation of Cell Growth in Response to Morphogenetic and Genotoxic Signals

“…In nearly all known NTD mutants examined, NTD arises from a failure to complete the process of elevation of the neural folds to become vertical. Neural fold elevation has been shown to be dependent on the proliferation of the neural fold and/or the underlying mesoderm because reduced mitosis in these tissues is associated with NTDs in Twist, Pax1/PDGFR␣, Pax1/foxc2, Shh, and Opb mutants (5,6,17,23,28). It is therefore likely that Hipks mediate neural fold elevation by regulating mitosis in the neural folds and/or underlying mesoderm, which may involve the Shh signaling cascade (66).…”

“…RNA in situ hybridization, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) with an in situ cell death detection kit (AP; Roche), bromodeoxyuridine (BrdU) incorporation analysis, and skeletal preparations were all performed as described previously (23).…”

Expression of FoxC, FoxF, FoxL1, and FoxQ1 genes in the dogfish Scyliorhinus canicula defines ancient and derived roles for fox genes in vertebrate development

“…In this study, we survey the diversity of Clustered Fox genes in the dog- (Buchberger et al, 1998;Koster et al, 1998;Winnier et al, 1999;Topczewska et al, 2001b (Buchberger et al, 1998;Hiemisch et al, 1998;Koster et al, 1998;Topczewska et al, 2001b) Intermediate mesoderm Yes Zebrafish, Xenopus, mouse (Koster et al, 1998;Kume et al, 2000;Topczewska et al, 2001b) Head mesoderm Yes Zebrafish, Xenopus, chicken, mouse (Sasaki and Hogan, 1993;Kaestner et al, 1996;Iida et al, 1997;Buchberger et al, 1998;Koster et al, 1998;El-Hodiri et al, 2001;Topczewska et al, 2001b) Sclerotome Yes Chicken, mouse (Buchberger et al, 1998;Hiemisch et al, 1998 (Buchberger et al, 1998;Hiemisch et al, 1998;Koster et al, 1998;Topczewska et al, 2001b) Heart No Xenopus, chicken, mouse (Buchberger et al, 1998;Koster et al, 1998;Winnier et al, 1999 Xenopus, chicken, mouse (Buchberger et al, 1998;Hiemisch et al, 1998;Koster et al, 1998;Topczewska et al, 2001b) Mouse (limb) (Furumoto et al, 1999) …”

New Mutant Mouse with Skeletal Deformities Caused by Mutation in Delta Like 3 (Dll3) Gene.

“…Particularly, a number of mutant mouse strains showing vertebral abnormalities have been reported. These mutant strains include brachyury [18], tail-short [28], undulated [12], curly-tail [14], crinkly-tail [23], meander tail [19], truncate [31], pudgy [16], tail kinks [15], and flexed-tail [20], which are useful animal models for investigating the developmental mechanisms of vertebral formation. For example, brachyury (T) is the classical mutant mouse showing tailless phenotype, which is associated with chromosomal inversion [30].…”

“…The causative gene for brachyury has been identified as an essential gene in mesoderm formation and thus this mutant mouse has been an excellent tool for studying processes underlying mesoderm formation in the mammals [18]. Many other genes controlling vertebral formation of mam-mals have been identified by investigating mutant mouse strains [12,25]. Furthermore, various knockout mice with targeted disruption of particular genes showing skeletal abnormalities have been reported [10,22,24,33,34].…”