Elevated SOX21 Expression in PROP1-Deficient Mice: A Novel Candidate Gene for Combined Pituitary Hormone Deficiency (CPHD)

CHEUNG L; BRINKMEIER ML; MORTENSEN AH; MARÍA INÉS PÉREZ MILLÁN; CAMPER SA

San Diego, CA

Congreso; The Endocrine Society´s Annual Meeting; 2015

Combined pituitary hormone deficiency (CPHD), or panhypopituitarism, is one of the most common forms of dwarfism, occurring in approximately 1 in every 4000 births (1). CPHD causes severe short stature due to reduction in pituitary growth hormone (GH), and may cause other health problems such as hypothyroidism, infertility, or adrenal insufficiency. More than half of CPHD cases have no known etiology, but mutations in the transcription factor PROP1 are the most frequent identified cause (2). PROP1 is a direct transcriptional regulator of two other genes which, when mutated, can cause CPHD. For this reason, we sought to identify genes that are differentially expressed in the pituitaries of Prop1 mutant mice (Prop1df/df). We found that the transcription factors Sox2 and Sox21 are both upregulated in Prop1 mutants. These genes have roles in regulation of stem cells and cell fate in a variety of tissues (3-5). SOX2 is a marker for pituitary stem cells, but nothing is known about the role of SOX21 in the pituitary gland. We have characterized the expression pattern of Sox21 in hypothalamic-pituitary development, and investigated its function using loss- and gain-of-function mouse models (6). We detect SOX21 expression in the developing neural ectoderm and adult hypothalamus, including the arcuate and paraventricular nuclei. Expression was not detectable during pituitary organogenesis, indicating that Prop1 deficiencyinduces ectopic Sox21 expression. Sox21-/- mice are normally sized at birth, but are severely dwarfed by 1 month of age, with no evidence for sexual dimorphism in growth. SOX21-deficient pituitary glands are smaller than their wild-type counterparts, due to reduced size of the lateral wings of the anterior lobe. GH cells, as well as other pituitary hormone cell-types, are present in SOX21-null pituitary glands at 1 and 4 months of age. GHRH axon terminals are present in the median eminence of Sox21-/- mice, and expression of liver insulin-like growth factor 1 (Igf-1) is similar between wild-type and mutant mice, suggesting GH release and signaling are intact. We are evaluating hypothalamic-pituitary-thyroid axis function for a contribution to the growth insufficiency, and exploring the development and function of other organs regulated by hypothalamic-pituitary axes. To determine whether ectopic Sox21 expression contributes to the arrested pituitary development characteristic of Prop1 mutants, we are developing a mouse model with inducible SOX21 overexpression. Our studies indicate that PROP1 normally represses SOX2 and SOX21, and suggest that ectopic SOX21 expression could be a contributor to hypopituitarism and growth insufficiency.