Genetic control of pituitary development and hypopituitarism

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The pituitary gland functions as a relay between the hypothalamus and peripheral target organs that regulate basic physiological functions, including growth, the stress response, reproduction, metabolism and lactation. The development of the pituitary gland has been studied extensively in mice, and has begun to be explored in zebrafish, an animal model system amenable to forward genetics. Multiple signaling molecules and transcription factors, expressed in overlapping but distinct spatial and temporal patterns, are required at various stages of pituitary development. Defects in this precisely regulated genetic program lead to diverse pituitary dysfunction. The animal models have greatly enhanced our understanding of molecular mechanisms underlying pituitary development in addition to congenital pituitary disorders in humans.

Introduction

The pituitary gland is composed of two anatomically and functionally distinct entities: the adenohypophysis, including the anterior and intermediate lobes; and the neurohypophysis, also known as the posterior lobe. As the primary site of endocrine action, the adenohypophysis contains six different cell types, which are characterized by the different hormones they produce and secrete: corticotropes, secreting ACTH (adrenocorticotrophic hormone); thyrotropes, secreting TSH (thyroid-stimulating hormone); somatotropes, secreting GH (growth hormone); lactotropes, secreting PRL (prolactin); gonadotropes secreting LH (luteinizing hormone) and FSH (follicle-stimulating hormone); and intermediate lobe melanotropes, secreting MSH (melanocyte-stimulating hormone). In humans, the intermediate lobe is greatly reduced in structure and function. In contrast to the adenohypophysis, the neurohypophysis does not contain endocrine cells. It secrets oxytocin and vasopressin, which are synthesized by supra-optic and paraventricular nuclei of the hypothalamus, and transported to axonal terminals located in the posterior lobe. The proper function of the pituitary is regulated by the hypothalamus, which secretes trophic factors that modulate cell proliferation, hormone synthesis and secretion.

In this review, we focus on recent advances in our understanding of the functions of transcription factors in pituitary development and human disorders.

Section snippets

Embryonic pituitary development

The adenohypophysis and neurohypophysis arise from different embryological tissues. Fate mapping by various means in frogs, chickens, mice and rats has shown that the adenohypophysis originates from midline cells in the anterior neural ridge, immediately anterior to the cells in the neural plate that give rise to the endocrine hypothalamus and the posterior lobe. In zebrafish, the adenohypophysis precursors are bilaterally distributed before they migrate and converge at the midline. In most

Human hypopituitarism and transcription factors

Hypopituitarism is the deficiency of any one or multiple pituitary hormones. Mutations in some of the transcription factors crucial for pituitary development have been identified in human patients with hypopituitarism. Mutations in transcription factors required for Rathke's pouch formation, cell proliferation or the differentiation of multiple cell lineages are associated with combined pituitary hormone deficiency (CPHD), and mutations in transcription factors required for the differentiation

Conclusions

Several signaling molecules and transcription factors that have not been discussed here are required for proper pituitary development and function (Table 2). Identification of mutations associated with pituitary hormone deficiency in theses candidate genes will confirm the findings in animal models and help us comprehend the structure–function relationships of these factors. The list of genes involved in pituitary development will grow — given the advances in genetic and molecular approaches.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We apologize to our colleagues whose contribution could not be cited owing to space limitations. We thank W Wu for helpful suggestions, and M Fisher and J Hightower for manuscript and figure preparation. MGR is an investigator with the Howard Hughes Medical Institute. Studies in the MGR laboratory are supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

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