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.

Heterozygous defects in PAX6 gene and congenital hypopituitarism

“…The proliferation and terminal differentiation of the anterior pituitary gland are strongly influenced by the precise spatial and temporal expression of transcription factors (1,2,3). Mutations in these transcription factors result in various types of congenital hypopituitarism (CH), ranging from isolated growth hormone deficiency (IGHD) to multiple pituitary hormone deficiency (MPHD) (1,2,3).…”

“…Mutations in these transcription factors result in various types of congenital hypopituitarism (CH), ranging from isolated growth hormone deficiency (IGHD) to multiple pituitary hormone deficiency (MPHD) (1,2,3). 165 MPHD patients from the international GENHYPOPIT network.…”

Role of GLI2 in hypopituitarism phenotype

“…Hypopituitarism may manifest as a deficiency of a single pituitary hormone, such as isolated growth hormone deficiency (IGHD) or combined pituitary hormone deficiency (CPHD), and it may be congenital or acquired (Kelberman et al 2009). Congenital hypopituitarism may have a genetic, environmental or combined aetiology.…”

“…Knowledge about genetic causes of congenital hypopituitarism has been advanced by the study of pituitary embryogenesis in animal models (natural and transgenic) and by candidate gene analysis in patients with pituitary hormone deficiencies. Although animal models have been very useful, one has to bear in mind that there may be differences when the results are extrapolated to the human (Kelberman et al 2009). …”

Transcription factor 7-like 1 is involved in hypothalamo–pituitary axis development in mice and humans

“…WNT pathway | pituitary | Tcf7l1 | septooptic dysplasia | hypopituitarism C ongenital hypopituitarism (CH) is a complex condition defined by the deficiency of one or more pituitary hormones and can be present in isolation or as part of a syndrome (1)(2)(3). Septooptic dysplasia (SOD) is a rare form of CH (1 in 10,000) that manifests in conjunction with defects in the telencephalon (e.g., corpus callosum and septum pellucidum) and/or eyes (e.g., optic nerve hypoplasia) and is associated with high morbidity and occasional mortality (4).…”