Fig. 8.

Our proposed model for the roles and interactions of Smad1/Smad5 in AER and ventral ectoderm of developing limbs. (A) Smad1 and Smad5 functions redundantly as the intracellular mediator of the BMP signaling downstream of BmprIa in the AER and ventral ectoderm (Maatouk et al., 2009; Pajni-Underwood et al., 2007). Fgf8 expression at the AER serves as cell survival signal to the interdigital mesenchyme (arrow). Smad1/5 signaling at the AER and ventral ectoderm inhibits Fgf8 expression. The termination of Fgf8 expression initiates programmed cell death in the intedigital mesenchyme. BMP signaling within the mesenchyme was shown to regulate interdigital PCD (Bandyopadhyay et al., 2006). (B) Inactivation of Smad1/Smad5 in the AER and ventral ectoderm would result in persisted Fgf8 expression. Fgf8 is expressed ectopically in the AER over interdigital region that leads to inhibition of PCD and ectopic cell survival and proliferation in the interdigital mesenchyme. In addition, there is an auto-regulatory loop of BMP signaling and BMP signals in the limb AER. In the absence of Smad1/5 signaling, BMP signals in the AER is elevated.