The Mn1 transcription factor acts upstream of Tbx22 and preferentially regulates posterior palate growth in mice

The mammalian secondary palate exhibits morphological, pathological and molecular heterogeneity along the anteroposterior axis. Although the cell proliferation rates are similar in the anterior and posterior regions during palatal outgrowth, previous studies have identified several signaling pathways and transcription factors that specifically regulate the growth of the anterior palate. By contrast, no factor has been shown to preferentially regulate posterior palatal growth. Here, we show that mice lacking the transcription factor Mn1 have defects in posterior but not anterior palatal growth. We show that Mn1 mRNA exhibits differential expression along the anteroposterior axis of the developing secondary palate, with preferential expression in the middle and posterior regions during palatal outgrowth. Extensive analyses of palatal gene expression in wild-type and Mn1^-/- mutant mice identified Tbx22, the mouse homolog of the human X-linked cleft palate gene, as a putative downstream target of Mn1 transcriptional activation. Tbx22 exhibits a similar pattern of expression with that of Mn1 along the anteroposterior axis of the developing palatal shelves and its expression is specifically downregulated in Mn1^-/- mutants. Moreover, we show that Mn1 activated reporter gene expression driven by either the human or mouse Tbx22 gene promoters in co-transfected NIH3T3 cells. Overexpression of Mn1 in NIH3T3 cells also increased endogenous Tbx22 mRNA expression in a dose-dependent manner. These data indicate that Mn1 and Tbx22 function in a novel molecular pathway regulating mammalian palate development.