Abstract

Sox2 mutations are associated with pituitary hormone deficiencies and the protein is required for pituitary progenitor proliferation, but its function has not been well characterized in this context. SOX2 is known to activate expression of Six6, encoding a homeodomain transcription factor, in the ventral diencephalon. Here, we find that the same relationship likely exists in the pituitary. Moreover, because Six6 deletion is associated with a similar phenotype as described here for loss of Sox2, Six6 appears to be an essential downstream target of SOX2 in the gland. We also uncover a second role for SOX2. Whereas cell differentiation is reduced in Sox2 mutants, some endocrine cells are generated, such as POMC-positive cells in the intermediate lobe. However, loss of SOX2 here results in complete downregulation of the melanotroph pioneer factor PAX7, and subsequently a switch of identity from melanotrophs to ectopic corticotrophs. Rescuing proliferation by ablating the cell cycle negative regulator p27 (also known as Cdkn1b) in Sox2 mutants does not restore melanotroph emergence. Therefore, SOX2 has two independent roles during pituitary morphogenesis; firstly, promotion of progenitor proliferation, and subsequently, acquisition of melanotroph identity.

Highlights

  • Pituitary endocrine secretions are regulated by the hypothalamus, located within the ventral diencephalon (VD)

  • Deletion of Sox2 in Rathke pouch (RP) results in reduction of progenitor proliferation SOX2 is expressed throughout RP at 10.5 dpc, becoming gradually restricted to the cells lining the cleft as development progresses (Fauquier et al, 2008)

  • Heterozygous loss-of-function mutations in SOX2 in humans are associated with severe eye defects, ranging from micropthalmia to anopthalmia, but affected individuals exhibit other congenital defects including hypopituitarism that can affect everything from height to puberty (Macchiaroli et al, 2014; Suzuki et al, 2014)

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Summary

Introduction

Pituitary endocrine secretions are regulated by the hypothalamus, located within the ventral diencephalon (VD). The two organs are connected through the pituitary stalk, allowing transmission of information between the two components of the axis. The hypothalamus integrates peripheral information and regulates pituitary secretions . The gland comprises three lobes, anterior, intermediate and posterior; endocrine cell types are located in the anterior (AL) and intermediate (IL) lobes, whereas the posterior lobe comprises hypothalamic axon termini and glial cells. Secreted hormones control the function of other endocrine glands, and different tissues. They are required for normal function of the organism as they intervene in many different physiological processes, including growth, reproduction, metabolism and response to stress.

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