Signaling and epigenetic regulation of pituitary development

Abstract

The developing pituitary gland provides an instructive model system for elucidating the molecular mechanisms by which distinct cell types arise from a common progenitor lineage accompanied by changes in the chromatin status in response to multiple extrinsic and intrinsic signals. Recent studies have shed light on the integration between signaling molecules and activation of transcription factors that are essential for cell-fate commitment and terminal differentiation. Investigation of the in vivo function of the histone modifying enzyme LSD1 has revealed a new layer of regulatory mechanism in pituitary organogenesis. Epigenetic studies of the transcriptional events in terminal differentiation process have provided insights into the functions of non-coding RNA and developmentally regulated chromatin organization.

Figure 1

Ontogeny of signaling molecules and selected transcriptional factors during mouse pituitary organogenesis. Ventral diencephalon, which expresses BMP4, FGF8/10/18 and Wnt5, makes direct contact with oral ectoderm and induces the formation of Rathke’s pouch. The opposing dorsal FGF and ventral BMP2 gradients convey proliferative and positional cues by regulating combinatorial patterns of transcription factor gene expression. Pit1 is induced at e13.5 in the caudomedial region of the pituitary gland, which ultimately gives rise to somatotropes (S), lactotropes (L) and thyrotropes (T). Corticotropes (C) and gonadotropes (G) are differentiated in the most ventral region of the gland. The dorsal portion of the Rathke’s pouch becomes the intermediate lobe, containing melanotropes (M). The infundibulum of the ventral diencephalon grows downward and eventually becomes the posterior lobe (P) of the gland. The functions of a number of signaling molecules, transcription factors, and cofactors regulating lineage commitment and terminal differentiation of distinct cell types are delineated in a genetic pathway.

Figure 2

Model of the roles of distinct LSD1-containing complexes during pituitary organogenesis. LSD1 activates a cohort of gene targets, including GH expression in somatotropes, by functioning as a component of the MLL1-containing coactivator complex. In postnatal lactotropes, a signal-induced expression of ZEB1, LcoR, and PC2 recruits the LSD1-containing CtBP-CoREST corepressor complex to the GH promoter and represses its expression.

Figure 3

Models of the human (A) and murine GH locus (B) activation. In the human GH locus, a Pit1-dependent LCR, encompassing the pituitary-specific DNase I hypersensitive site (HS) I, is required for the expression of intergenic non-coding RNAs, the establishment of hyperacetylated chromatin domain, and the hGH-N transgene expression. Transcription of the intergenic non-coding RNAs also contributes to the downstream hGH-N transgene activation. In the murine GH locus, an upstream SINE B2 repeat, which can function as a boundary element in cells, is necessary for the transgene expression. At E14.5 during pituitary development, transcription from the Pol II promoter of the SINE B2 repeat occurs concurrently with transition of the GH locus from heterochromatin domain to euchromatin domain.