A dynamic Gli code interprets Hh signals to regulate induction, patterning, and endocrine cell specification in the zebrafish pituitary

Abstract

Hedgehog (Hh) signaling is necessary for the induction and functional patterning of the pituitary placode, however the mechanisms by which Hh signals are interpreted by placodal cells are unknown. Here we show distinct temporal requirements for Hh signaling in endocrine cell differentiation and describe a dynamic Gli transcriptional response code that interprets these Hh signals within the developing adenohypophysis. Gli1 is required for the differentiation of selected endocrine cell types and acts as the major activator of Hh-mediated pituitary induction, while Gli2a and Gli2b contribute more minor activator functions. Intriguingly, this Gli response code changes as development proceeds. Gli1 continues to be required for the activation of the Hh response anteriorly in the pars distalis. In contrast, Gli2b is required to repress Hh target gene expression posteriorly in the pars intermedia. Consistent with these changing roles, gli1, gli2a, and gli2b, but not gli3, are expressed in pituitary precursor cells at the anterior neural ridge. Later in development, gli1 expression is maintained throughout the adenohypophysis while gli2a and gli2b expression are restricted to the pars intermedia. Given the link between Hh signaling and pituitary adenomas in humans, our data suggest misregulation of Gli function may contribute to these common pituitary tumors.