Figure 8. An autoregulatory polarising region cell cycle timer.

(a) Shh signalling is required for Cyclin D2 expression in the polarising region (green). Bmp2 signalling acts downstream of Shh to control p27^kip1 that inhibits the D-cyclin-dependent formation of a digit from the polarising region (X), and that also promotes the digit 2 to digit 3 positional value in adjacent cells. Shh signalling also stimulates Cyclin D1-dependent proliferation in the digit-forming field, which is required for the progressive specification of antero-posterior digit positional values - 1, 2 and then 3, over 12 hr. (b) Inhibition of Shh signalling during digit specification prevents Bmp2 signalling from promoting the digit 2 to digit 3 positional value in the digit-forming field adjacent to the polarising region. In addition, loss of Bmp2 signalling prevents p27^kip1 from inhibiting polarising region proliferation and digit development. Since blocking Shh signalling attenuates Cyclin D2 function, Cyclin D1 is likely to be responsible for the over-proliferation of polarising region cells.