We hypothesize that CN injury-induced apoptosis is caused by decreased SHH protein. A mechanism for SHH involvement in apoptosis induction in the penis is presented in detail below, based on what is known about the Shh signaling pathway in the penis and in other organs (Fig. 9). In the absence of SHH, caspase 3 activity is increased and the G1 to S transition is inhibited, which leads to apoptosis which can be prevented by SHH application. The cell death program is initiated by the proapoptotic dependence receptor PTCH1.
This requires preliminary cleavage of PTCH1 ‘s intracellular domain by caspase enzymes (caspase 3 and less frequently caspase 7 and 8 ) and exposes the carboxyl-terminal apoptotic domain. Transfecting cultured cells with the carboxy-terminal region of Ptchl is sufficient to induce cell death, increased TUNEL staining is associated with Ptchl over expression, and SHH treatment can inhibit PTCH1-induced cell death in a dose-dependent manner. When SHH is inhibited, PTCH1 inhibits SMO, which causes the formation of GLI3 in a truncated repressor form. Bmp4 is elevated in response to truncated GLI3 during limb development and is associated with elevated apoptosis in several systems.