Genetic regulation of pituitary gland development in human and mouse

Abstract

Normal hypothalamopituitary development is closely related to that of the forebrain and is dependent upon a complex genetic cascade of transcription factors and signaling molecules that may be either intrinsic or extrinsic to the developing Rathke's pouch. These factors dictate organ commitment, cell differentiation, and cell proliferation within the anterior pituitary. Abnormalities in these processes are associated with congenital hypopituitarism, a spectrum of disorders that includes syndromic disorders such as septo-optic dysplasia, combined pituitary hormone deficiencies, and isolated hormone deficiencies, of which the commonest is GH deficiency. The highly variable clinical phenotypes can now in part be explained due to research performed over the last 20 yr, based mainly on naturally occurring and transgenic animal models. Mutations in genes encoding both signaling molecules and transcription factors have been implicated in the etiology of hypopituitarism, with or without other syndromic features, in mice and humans. To date, mutations in known genes account for a small proportion of cases of hypopituitarism in humans. However, these mutations have led to a greater understanding of the genetic interactions that lead to normal pituitary development. This review attempts to describe the complexity of pituitary development in the rodent, with particular emphasis on those factors that, when mutated, are associated with hypopituitarism in humans.

Figure 1

Mouse pituitary development in sagittal section. Stages of development are indicated in dpc. AL, Anterior lobe; AN, anterior neural pore; DI, diencephalon; F, forebrain; H, heart; HB, hindbrain; I, infundibulum; IL, intermediate lobe; MB, midbrain; N, notochord; NP, neural plate; O, oral cavity; OC, optic chiasma; OM, oral membrane; P, pontine flexure; PL, posterior lobe; PO, pons; PP, prechordal plate; RP, Rathke’s pouch; SC, sphenoid cartilage. [Adapted from H. Z. Sheng and H. Westphal: Trends Genet 15:236–240, 1999 (317), with permission from Elsevier.]

Figure 2

Schematic representation of the developmental cascade of genes implicated in human pituitary development with particular reference to pituitary cell differentiation.

Figure 3

Midline sagittal hematoxylin and eosin-stained sections showing pituitary organogenesis during human embryonic development. A, Midline sagittal section of a Carnegie stage (CS) 13 embryo (approximately 5 wk of development) showing the invagination of the oral ectoderm to form Rathke’s pouch (arrow). B, Sagittal section of CS14 embryo showing the developing Rathke’s pouch (Rp) coming into contact with the overlying neuroectoderm. C, Sagittal section of CS15 embryo showing the definitive Rathke’s pouch becoming separated from the oral ectoderm (oe). D, Definitive Rathke’s pouch (Rp) shown in sagittal section fully separated from the oral ectoderm maintaining contact with the neural ectoderm of the diencephalon (Di) at CS17. Scale bars: A and D, 300 μm; B and C, 100 μm. [Images were kindly provided courtesy of D. Gerrelli, Medical Research Council-Wellcome Trust Developmental Biology Resource, University College London Institute of Child Health, London, United Kingdom.]

Figure 4

A, Midsagittal MRI scan of the head of a normal child. Note the well-formed corpus callosum (CC), the optic chiasm (OC), and the posterior pituitary (PP), which appears as a bright spot within the sella turcica. B, Sagittal MRI scan of two siblings with a homozygous p.R160C mutation in HESX1. In the first sibling (i) the splenium of the corpus callosum is more hypoplastic than the rest of the structure and the posterior pituitary is partially descended as compared with the other sibling (ii) who has a severely hypoplastic corpus callosum, ectopic posterior pituitary, and lack of visible pituitary stalk (PS). C, Coronal and sagittal MRI scans from one patient [panels (i) and (ii)] and sagittal scan from a second patient (iii) with SOX3 duplication showing anterior pituitary (AP) hypoplasia, partial hypoplasia of the infundibulum (I) in the first patient, which is completely absent in the second, and an ectopic posterior pituitary which is more severe in patient 2. D, MRI scan from patients with SOX2 mutations. Sagittal section from patient with c60insG mutation showing anterior pituitary (ap) hypoplasia with normal posterior pituitary (pp) and infundibulum (i) and a hypothalamic hamartoma (h). E, Sagittal MRI scan in patient with compound heterozygosity for p.E230K and p.R172Q mutations in POU1F1, showing hypoplasia of the anterior pituitary gland with a normal posterior pituitary and infundibulum. F, Sequential MRI scanning of a patient with a 13-bp deletion (c.112_124del13) in PROP1 reveals waxing and waning of a pituitary mass (arrow); (i) on initial presentation, (ii) after 4 months, (iii) after 12 months, and (iv) 21 months after initial MRI. [Panels A and B were derived from Brickman et al. (200); panel C was derived from Woods et al. (220) and reproduced with permission from Elsevier (University of Chicago Press); panel D was derived from Kelberman, et al. (103) and reproduced with permission from the American Society for Clinical Investigation. Panels E (copyright 2005, The Endocrine Society) and F, derived from Turton et al. (Refs. and , respectively), were reproduced with permission.]