A role of the LIM-homeobox gene Lhx2 in the regulation of pituitary development

Abstract

The mammalian pituitary gland originates from two separate germinal tissues during embryonic development. The anterior and intermediate lobes of the pituitary are derived from Rathke's pouch, a pocket formed by an invagination of the oral ectoderm. The posterior lobe is derived from the infundibulum, which is formed by evagination of the neuroectoderm in the ventral diencephalon. Previous studies have shown that development of Rathke's pouch and the generation of distinct populations of hormone-producing endocrine cell lineages in the anterior/intermediate pituitary lobes is regulated by a number of transcription factors expressed in the pouch and by inductive signals from the ventral diencephalon/infundibulum. However, little is known about factors that regulate the development of the posterior pituitary lobe. In this study, we show that the LIM-homeobox gene Lhx2 is extensively expressed in the developing ventral diencephalon, including the infundibulum and the posterior lobe of the pituitary. Deletion of Lhx2 gene results in persistent cell proliferation, a complete failure of evagination of the neuroectoderm in the ventral diencephalon, and defects in the formation of the distinct morphological features of the infundibulum and the posterior pituitary lobe. Rathke's pouch is formed and endocrine cell lineages are generated in the anterior/intermediate pituitary lobes of the Lhx2 mutant. However, the shape and organization of the pouch and the anterior/intermediate pituitary lobes are severely altered due to the defects in development of the infundibulum and the posterior lobe. Our study thus reveals an essential role for Lhx2 in the regulation of posterior pituitary development and suggests a mechanism whereby development of the posterior lobe may affect the development of the anterior and intermediate lobes of the pituitary gland.

FGF-dependent midline-derived progenitor cells in hypothalamic infundibular development

“…However, in the mouse, SOX3 has been shown to play a crucial role in infundibular development (Rizzoti et al, 2004) which inappropriately high levels of proliferation are detected in the ventral diencephalic floor, with concomitant failure of infundibular evagination (Zhao et al, 2010). How SOX3 exerts its actions and the nature of SOX3 + cells remain unclear.…”

“…In zebrafish, FGF signalling is required for the expression of Lhx2 (Seth et al, 2006), a Lim homeodomain transcription factor that is expressed widely in the ventral hypothalamus and that in mouse is required for appropriate proliferation and formation of the infundibulum. Mouse mutants that lack LHX2 expression show unusually high levels of proliferation in the ventral diencephalic floor, with concomitant failure of infundibular evagination (Zhao et al, 2010). In Fgf10 knockout mice, furthermore, the infundibulum similarly fails to evaginate fully and infundibular cells undergo apoptosis (Ohuchi et al, 2000).…”

Screening of LHX2 in patients presenting growth retardation with posterior pituitary and ocular abnormalities

“…Rathke's pouch and infundibulum have a close contact during embryonic development and their differentiation depends on the sequential temporal and spatial expression of signaling molecules and transcription factors (1). Among them, three members of the LIM (Lin-11, Isl-1, and Mec-3) homeodomain protein family, LHX2, LHX3, and LHX4, participate in pituitary development (2,3). These transcription factors are made of a homeodomain and two zinc-finger LIM domains, which are involved in protein-protein interactions and may modulate the function of the homeodomain (4).…”

“…Lhx2 mRNA has been detected in the developing ventral diencephalon in mice (from e9.5) including the infundibulum and the posterior lobe of the pituitary gland (3), and its expression in the central nervous system persists in adulthood (7). The retina also evaginates from the neuroectoderm, and, before birth, Lhx2 is expressed throughout the neural retina, while postnatally, expression becomes restricted to the inner nuclear layer of the retina (8,9).…”

“…In mice, functional inactivation of Lhx2 results in a cerebral cortex of reduced size, anophthalmia, as well as absence of posterior pituitary gland and intermediary lobe, and defects in anterior pituitary lobe organization suggesting a mechanism whereby development of the posterior lobe may affect the development of the anterior and intermediate lobes of the pituitary gland. Lhx2 K/K mice also develop liver fibrosis; erythropoiesis is incomplete resulting in death by severe anemia before birth (3,8,11). Two studies performed in cohorts of patients with ocular abnormalities associated or not with schizencephaly did not permit to involve LHX2 in human pathology (14, 15).…”