Crosstalk between Sonic hedgehog and CRH pathways leading to a synergic effect on ACTH secretion

Sonic hedgehog (Shh) is a signaling protein important in regulating proliferation, survival and growth in the embryo and the adult. It is crucial during pituitary development, exerting effects on both proliferation and cell type determination. We studied for the first time the expression and function of this pathway in the normal pituitary. Shh is expressed in the normal pituitary being co-localised in corticotrophs. These cells posses also the receptor Patched 2 and the transcription factor Gli1, so they are Shh-producing and Shh-responding cells. Shh stimulates 3-fold the ACTH secretion from the rat pituitary in primary culture and this effect is synergic with CRH. The same results (but higher stimulation and synergism values) were obtained from the AtT-20 corticotrophinoma cell line.

Studying the mechanisms of Shh and CRH synergisms, we found out that Shh stimulation increases CRH-R1 levels, up-regulating so the response of corticotrophs to CRH. At the same time, Gli1, the transcription factor of the Shh pathway, is not only activated by Shh, but also by CRH and PKA. Gli1 itself activates POMC-transcription and acts in parallel upstream to CREB and AP-1. A major increase in Shh protein levels is seen as a result of CRH stimulation. All these results put in evidence a multiple crosstalk between these two important pathways acting at different levels to insure the final ACTH stimulation.