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Development of the Hypothalamus and Pituitary

المؤلف:  Wass, J. A. H., Arlt, W., & Semple, R. K. (Eds.).

المصدر:  Oxford Textbook of Endocrinology and Diabetes

الجزء والصفحة:  3rd edition , p112-113

2026-01-18

488

 In the diencephalic part of the forebrain vesicle the hypothalamus develops in the floor; the thalamus develops in the roof, and eye primordia in the lateral walls. Sonic hedgehog (Shh) secreted by the prechordal mesoderm situated below the ventral midline floor directs progenitors to hypothalamic and optic stalk fates but inhibits retinal differentiation (loss of Shh causes absent hypothalamus and cyclopia). A variety of transcription factors (including Nxk2.1, Nkx2.1, Rx, Six3) direct formation of the dorsal and ventral hypo thalamus. The hypothalamus shows extensive spatial patterning with neurons becoming organized into 12– 28 different nuclei. Wnt is critical in anterior- posterior patterning and BMP7 directs nu clear specification. With one exception (gonadotropin- releasing hormone (GnRH) neurons) there is little cell migration in and out of the hypothalamus after neurogenesis starts. Neurons in the lateral hypothalamic area are generated first, then neurons in the dorsomedial and ventromedial nucleus and finally those along the midline such as the arcuate nucleus. Gliogenesis occurs only after neurogenesis. GnRH neurons form from precursors which originate outside the CNS in the nasal placode and migrate in association with olfactory axon bundles. Once in the CNS, olfactory axons synapse in the olfactory bulb whereas GnRH neurons continue to migrate caudally on other axons to the hypothalamus. Mutation of a number of genes including KAL1 prevent this migration and cause Kallmann syndrome (anosmia with hypogonadotropic hypogonadism due to a failure of GnRH secretion).

The pituitary has a dual origin: the adenohypophysis (anterior lobe and intermediate zone) develops from ectoderm in the roof of the stomodeum which evaginates by week 3 of gestation to form Rathke’s pouch. The dorsal portion of Rathke’s pouch directly contacts the infundibulum which grows down from the floor of the developing hypothalamus to form the neurohypophysis (posterior lobe). When Rathke’s pouch becomes separated from the stomodeal ectoderm by the developing sphenoid bone, remnants of the pouch form the pharyngeal pituitary. The development and differentiation of the various pituitary endocrine cell types in volves the sequential and expression of several transcription fac tors, including PIT1 (POU1F1) and PROP 1. Corticotrophs are the earliest detectable fetal pituitary cell type, appearing by the eighth week of gestation. T- pit (Tbx19) has been identified as a critical transcription factor for both corticotroph cell differentiation and for POMC gene transcription (and subsequently melanotroph development in the intermediate zone). Prop- 1 and Pit- 1 direct the formation of somatotrophs and lactotrophs, and Pit- 1 and GATA- 2 that of most thyrotrophs. Finally, GATA- 2 with steroidogenic factor 1 (SF1) directs the formation of gonadotrophs. Mutations in the genes encoding these transcription factors can produce pituitary hypoplasia or agenesis, and a combined deficiency of pituitary hormones (GH, PRL, TSH, FSH, LH). Mutations in the gene encoding T- pit cause congenital isolated adrenocorticotropic hormone (ACTH) deficiency. Postnatally, cell turnover in the anterior pituitary is very slow and regulated by both hypothalamic and feedback factors. The number of somatotrophs doubles during puberty and the number and size of lactotrophs changes markedly during pregnancy, lactation, and weaning. Progenitor stem cells in the anterior pituitary have been difficult to define but candidates have included the cells which line the pituitary cleft and certain types of folliculo- stellate (F- S) cells. Recently a tiny population of SOX2- expressing cells in the adult pituitary has been shown to be capable of differentiating into all the endocrine and F- S cell types. Because of the immunochemical resemblance of some F- S cells to dendritic cells a bone marrow origin has been proposed for these cells but this remains to be confirmed. Much less is known about the control of the formation of the neurohypophysis, but it has recently been shown that both Hes1 and Hes5 are required both for the evagination of the infundibulum to form the posterior pituitary, and also for the formation of pituicytes.