September 16, 2008
In the early 1990s, Americans began hearing the advertising slogan, “Got Milk?” to remind them of the health benefits of drinking milk. If biologists were to co-opt this now clichéd line to explain human development, they might start with “Got Smad4?” This small molecule plays a pivotal role in the classic TGFβ/BMP signaling pathway that initiates the three-dimensional patterning of cells as they form the distinctive shapes of a tooth, palate (roof of the mouth), or other structures throughout the body.
In the August 12 issue of Developmental Cell, a team of NIDCR grantees turned the question around. They asked what happens to a growing tooth and palate in the fetal ectodermal layer when developing mice don't have Smad4? In the tooth, the researchers found the protein is required for the proper patterning of the cusps. But the lack of Smad4 doesn’t stop a tooth from forming. In the roof of the mouth, they found the palatal epithelium still fused - the normal developmental outcome - without Smad4 to mediate the process. Building on earlier reports that TGFβ/BMP might also signal independently of Smad4 via the nearby p38 protein, they inactivated both p38 and Smad4 and saw the dramatic developmental defects of blocking TGFβ/BMP that neither missing protein could cause alone. This led the scientists to conclude that ectodermal Smad4 and p38 are functionally redundant in mediating the TGFβ/BMP signaling pathway during tooth and palate development.