Loss of steroidogenic factor 1 alters cellular topography in the mouse ventromedial nucleus of the hypothalamus

Abstract

Knockout (KO) mice lacking the orphan nuclear receptor steroidogenic factor 1 (SF-1) exhibit marked structural abnormalities of the ventromedial nucleus of the hypothalamus (VMH). In this study, we sought to determine the molecular mechanisms underlying the VMH abnormalities. To trace SF-1-expressing neurons, we used a SF-1/enhanced green fluorescent protein (eGFP) transgene. Although the total numbers of eGFP-positive cells in wild-type (WT) and SF-1 KO mice were indistinguishable, cells that normally localize precisely within the VMH were scattered more diffusely in adjacent regions in SF-1 KO mice. This abnormal distribution is likely due to the loss of SF-1 expression in VMH neurons rather than secondary effects of deficient steroidogenesis, as redistribution also was seen in mice with a CNS-specific KO of SF-1. Thus, the absence of SF-1 alters the distribution of cells that normally form the VMH within the mediobasal hypothalamus. Consistent with this model, the hypothalamic expression patterns of the transcription factors islet-1 and nkx2.1 also were displaced in SF-1 KO mice. Independent of gene expression, birthdate analyses further suggested that cells with earlier birthdates were affected more severely by the loss of SF-1 than were later born cells. We conclude that the absence of SF-1 causes major changes in cellular arrangement within and around the developing VMH that result from altered cell migration.

Deletion of theTtf1Gene in Differentiated Neurons Disrupts Female Reproduction without Impairing Basal Ganglia Function

“…4g,h). As expected, loss of TTF1 mRNA was evident in both the ventromedial and arcuate nucleus, two neuronal sites of postnatal TTF1 expression in the hypothalamus (Lee et al, 2001;Davis et al, 2004). In contrast, TTF1 mRNA and protein levels appeared to be unchanged in the ME and ependymoglial cells of the ME (Fig.…”

“…Such a role might extend to postnatal life, because TTF1 remains expressed after birth in selected striatal/pallidum interneurons (Marin et al, 2000), as well as in defined glial and neuronal subsets of the hypothalamus and the POA (Lee et al, 2001). Specifically, TTF1 is detected in POA neurons that control repro-ductive function via release of the peptide luteinizing hormone (LH)-releasing hormone (LHRH) (Lee et al, 2001), in preproenkephalinergic neurons of the lateral ventromedial nucleus (Lee et al, 2001;Davis et al, 2004), which restrain the initiation of puberty by transsynaptically inhibiting LHRH neurons (Ojeda and Skinner, 2006), in unidentified neurons of the arcuate nucleus, and in ependymoglial cells of the third ventricle and median eminence (ME). The ME is the final common pathway for LHRH neuronal axons converging to release LHRH into the portal system that connects the hypothalamus to the pituitary gland (Silverman et al, 1994).…”

The Neonatal Ventromedial Hypothalamus Transcriptome Reveals Novel Markers with Spatially Distinct Patterning

“…Of these transcription factors, known roles in hypothalamic development have been described only for SF-1 and Nkx2.1. Although SF-1 is not required for the birth of VMH neurons and is expressed only in postmitotic neurons (Tran et al, 2003), SF-1 is required for maintenance of normal VMH cytoarchitecture (Ikeda et al, 1995;Shinoda et al, 1995), for terminal differentiation (Tran et al, 2003), and proper condensation of the VMH nucleus (Davis et al, 2004). In the adult, these developmental deficits have been indirectly linked to energy dysregulation as evidenced by the fact that adrenal rescued Sf-1 null adult mice display obesity (Majdic et al, 2002), and SF-1 heterozygous mice have decreased hypothalamic sympathetic output with a propensity for diet-induced obesity (Tran et al, 2006).…”

Neuronal control of energy homeostasis

“…In contrast, a selective deletion of the leptin receptor gene in the neurons that express steroid factor-1 (SF-1) in the VMH results in mice that are not only obese but also hyperphagic [66,67]. SF-1 is a transcription factor necessary for the development of the VMH [68][69][70]. Mice with mutations to leptin receptors in both the ARC POMC and the VMH SF1 neurons are more obese than those with mutations of leptin receptors in either set of neurons alone [67].…”