The function and regulation of TBX22 in avian frontonasal morphogenesis

Abstract

The frontonasal mass gives rise to the facial midline and fuses with the maxillary prominence to form the upper lip. Here we focus on the regulation and function of TBX22, a repressor dynamically expressed in the frontonasal mass. Both FGF and Noggin (a BMP antagonist) strongly induce gTBX22, however, each has opposite effects on morphogenesis -Noggin inhibits whereas FGF stimulates growth. To determine whether TBX22 mediates these effects, we used retroviruses to locally increase expression levels. RCAS::hTBX22 decreased proliferation, reduced expression of MSX2 and DLX5 and caused cleft lip. Decreased levels of endogenous gTBX22 were also observed but were not the primary cause of the phenotype as determined in rescue experiments. Our data suggest that genetic or environmental insults such as those affecting the BMP pathway could lead to a gain-of-function of TBX22 and predispose an individual to cleft lip. Developmental Dynamics 239:458-473,

Regulation of Tbx22 during facial and palatal development

“…By stage 26, TBX22 expression in the developing palate becomes independent of FGF signaling, while it still responds to repression by BMP4. These findings are in line with the results of Higashihori et al (2010) who also showed that TBX22 expression in the chicken frontonasal mass is induced and maintained by FGF and negatively regulated by BMP signaling.…”

“…Nevertheless, the events downstream of these two pathways and their combined effects are so far only partially understood. A recent study by Higashihori et al (2010), published while this article was being assembled, demonstrated that TBX22 expression is regulated by both FGF and BMP pathways during development of the chicken frontonasal mass. Here we confirm their findings and, in addition, show that these two pathways also regulate TBX22 expression during development of the secondary palate.…”

“…Taken together, our analyses in the mouse and chick thus suggest that MSX1 does not repress Tbx22 directly. Given the high homology between MSX1 and MSX2, an inhibitory effect of MSX2 on TBX22, as discussed by Higashihori et al (2010), also seems unlikely.…”

“…To further address the function of TBX22 in facial development, Higashihori et al (2010) misexpressed human TBX22 on one side of the developing chicken face. This manipulation resulted in reduced cell proliferation, a downregulation of DLX5, MSX2, and the endogenous TBX22, and the development of a cleft beak.…”

“…The upstream regulation of Tbx22 expression and its integration into the molecular network regulating facial and palatal development, however, is less well understood. Higashihori et al (2010) recently demonstrated that TBX22 expression in the chicken frontonasal mass is positively regulated by FGF signaling and inhibited by BMP signaling. They, furthermore, showed that misexpression of human TBX22 resulted in decreased proliferation in frontonasal mesenchyme, reduced expression of MSX2 and DLX5, and a cleft beak phenotype.…”