Genes important in the fetal development of the pituitary

Pituitary development is coordinated by the timely interaction of several signaling pathways and transcription factors. The expression of lhx3 precedes that of transcription factors like tbx19, prop1, gata2 or sf1 and requires earlier expression of others like pitx1 and pitx2 and pathways like sonic hedgehog. The adult pituitary contains SOX2/SOX9 positive pituitary stem cells and progenitors leading to a differentiated pituitary, and in vitro differentiation of embryonic stem cells into mature pituitary cells was shown to recapitulate anterior pituitary development. Conditional inactivation of isl-1 in thyrotrophs induces central hypothyroidism, showing that this LIM domain factor is necessary for thyrotroph function. Large scale genomic techniques identified new pathogenic gene variants in constitutional hypopituitarism, an indirect evidence of their role in pituitary development or function: a variant of GPR161 was identified by whole exome sequencing in GH deficiency; a variant of ARNT2 was associated with constitutional panhypopituitarism, diabetes insipidus and microcephaly. Allelic variations of NFKB2 were associated with pituitary deficiency (mainly ACTH deficiency) and variable immune deficiency (VID), described as DAVID syndrome. IGSF1 alterations were identified in a complex X-linked phenotype with thyrotroph deficiency, macro-orchidism, delayed puberty, transient GH or ACTH deficiency, and low prolactin levels. The first variants of the potassium channel gene KCNQ1 were reported in families with GH deficiency, gingival fibromatosis and arrhythmia. Thanks to new genome wide techniques, more causative genes have been identified over the past 6 years than over the 2 decades following the first identification of the role of pou1f1 in human hypopituitarism. Demonstrating the role of these new genes will require an appropriate cell model that may derive from novel stem cell techniques. Such approaches will help better understand pituitary development and functions.