Disruption of the gene encoding SF‐1 alters the distribution of hypothalamic neuronal phenotypes

Abstract

The ventromedial nucleus of the hypothalamus (VMH) in mice first emerges as a histologically distinct cell cluster around embryonic day 17 (E17). The earliest known marker for cells destined to form the VMH is the orphan nuclear receptor, steroidogenic factor 1 (SF-1), which can be detected in the hypothalamic primordium by E11. Strikingly, the VMH is absent in newborn SF-1 knockout mice, suggesting that SF-1 is essential for the development of VMH neurons. We reported previously that the VMH can be identified before it emerges as a histologically distinct nucleus (i.e., at E13) by the exclusion of cells that are immunoreactive for both gamma-aminobutyric acid (GABA) and the synthetic enzyme, glutamic acid decarboxylase (GAD67). Subsequently, by E15, the developing VMH is demarcated further by cells that are immunoreactive for neuropeptide Y, estrogen receptor alpha (ERalpha), and galanin. It is noteworthy that the normal exclusion of GABA from the developing VMH is not seen in SF-1 knockout mice, and cells that are immunoreactive for neuropeptide Y, ERalpha, and galanin also are distributed aberrantly in this region. Thus, the absence of SF-1 profoundly affects the cellular architecture of the VMH from early stages in its formation. These data suggest that, directly or indirectly, SF-1 plays important roles in determining the distribution of cells in the mediobasal hypothalamus.

Requirement of the orphan nuclear receptor SF-1 in terminal differentiation of ventromedial hypothalamic neurons

“…Previous studies proposed that the altered hypothalamic cytoarchitecture observed in sf-1 −/− mice might arise from the complete loss of VMN neurons due to cell death (Ikeda et al, 1995;Dellovade et al, 2000). However, TUNEL analysis revealed no apparent cell death in the presumptive VMN of both +/+ and −/− mice from E11 through postnatal day (P) 0 despite our ability to detect TUNEL-positive cells in the developing olfactory epithelium, as previously reported (Pellier and Astic, 1994;Voyron et al, 1999;and data not shown).…”

“…However, the presence of limited afferent projections from the mutant VMN area suggests that either terminal differentiation of a limited number of VMN neurons is not entirely dependent on SF-1 function, or alternatively, VMN precursors in mutant mice adopt neuronal fates of neighboring hypothalamic nuclei that also send axonal projections to the anterior hypothalamus. In this regard, Tobet and colleagues noted an expansion of neurons expressing ERα, galanin, and neuropeptide Y in the presumptive VMN of sf-1 −/− neonates (Dellovade et al, 2000). Normally, these peptides are selectively expressed in the neurons of lateral hypothalamus, dorsomedial nucleus, and arcuate nucleus, respectively.…”

“…Previous reports suggested that GABAergic neurons are expanded into the VMN as early as E15 in sf-1 −/− mice (Dellovade et al, 2000). Therefore, to examine a potential change in cell fate of VMN neurons, we analyzed GAD67 expression by in situ hybridization in the VMN of sf-1 −/− mice.…”

“…Impaired VMN development in sf-1 −/− mice was explained as either a failure of VMN aggregation and organization or the regression of VMN neurons at late stages of development, analogous to the prominent cell death accounting for adrenal and gonadal agenesis in sf-1 −/− mice (Ikeda et al, 1995;Shinoda et al, 1995). More recently, detailed histological analyses reported an expansion of glutamic acid decarboxylase (GAD) 67 and estrogen receptor (ER)α-positive neurons in the presumptive embryonic sf-1 −/− VMN, leading to the suggestion that VMN precursors either fail to aggregate, survive, or differentiate properly (Dellovade et al, 2000). Collectively, these studies suggest that SF-1 could participate in multiple phases of VMN development; early phases would include the proliferation, survival, and migration of VMN precursors from the ventricular zone, while later stages would involve the aggregation and condensation of the VMN nucleus.…”

Developmental expression of steroidogenic factor-1, cyp19a1a and cyp19a1b from common carp (Cyprinus carpio)

“…Previous research indicates that SF-1 play an important role in mammalian ventromedial nucleus development (Roselli et al, 1997;Fleming et al, 1999;Dellovade et al, 2000) and regulation of GTH expression in pituitary Ahmed, 1998;Bakke et al, 2001). We analyzed five regions of the carp brain including telecephalon, midbrain, cerebellum, and medulla oblongata, and found that SF-1 was expressed in the hypothalamus of both sexes (Fig.…”