Immunoglobulin superfamily, member 1 (IGSF1) is a transmembrane glycoprotein with high expression in the mammalian pituitary gland. Mutations in the IGSF1 gene cause congenital central hypothyroidism ...in humans. The IGSF1 protein is co-translationally cleaved into N- and C-terminal domains (NTD and CTD), the latter of which is trafficked to the plasma membrane and appears to be the functional portion of the molecule. Though the IGSF1-NTD is retained in the endoplasmic reticulum and has no apparent function, it has a high degree of sequence identity with the IGSF1-CTD and is conserved across mammalian species. Based upon phylogenetic analyses, we propose that the ancestral IGSF1 gene encoded the IGSF1-CTD, which was duplicated and integrated immediately upstream of itself, yielding a larger protein encompassing the IGSF1-NTD and IGSF1-CTD. The selective pressures favoring the initial gene duplication and subsequent retention of a conserved IGSF1-NTD are unresolved.
Inter-organ communication is a major hallmark of health and is often orchestrated by hormones released by the anterior pituitary gland. Pituitary gonadotropes secrete follicle-stimulating hormone ...(FSH) and luteinizing hormone (LH) to regulate gonadal function and control fertility. Whether FSH and LH also act on organs other than the gonads is debated. Here, we find that gonadotrope depletion in adult female mice triggers profound hypogonadism, obesity, glucose intolerance, fatty liver, and bone loss. The absence of sex steroids precipitates these phenotypes, with the notable exception of fatty liver, which results from ovary-independent actions of FSH. We uncover paracrine FSH action on pituitary corticotropes as a mechanism to restrain the production of corticosterone and prevent hepatic steatosis. Our data demonstrate that functional communication of two distinct hormone-secreting cell populations in the pituitary regulates hepatic lipid metabolism.
Abstract
Single same cell RNAseq/ATACseq multiome data provide unparalleled potential to develop high resolution maps of the cell-type specific transcriptional regulatory circuitry underlying gene ...expression. We present CREMA, a framework that recovers the full cis-regulatory circuitry by modeling gene expression and chromatin activity in individual cells without peak-calling or cell type labeling constraints. We demonstrate that CREMA overcomes the limitations of existing methods that fail to identify about half of functional regulatory elements which are outside the called chromatin ‘peaks’. These circuit sites outside called peaks are shown to be important cell type specific functional regulatory loci, sufficient to distinguish individual cell types. Analysis of mouse pituitary data identifies a Gata2-circuit for the gonadotrope-enriched disease-associated Pcsk1 gene, which is experimentally validated by reduced gonadotrope expression in a gonadotrope conditional Gata2-knockout model. We present a web accessible human immune cell regulatory circuit resource, and provide CREMA as an R package.
Graphical Abstract
Graphical Abstract
The pituitary gonadotropin hormones, FSH and LH, are key regulators of reproductive physiology. Though the two hormones are produced by the same cell type, often in response to the same endocrine and ...paracrine regulators, they sub-serve different biological functions and their synthesis and secretion are differentially regulated. This stems largely from differences in transcriptional, post-transcriptional, and post-translational regulation of their unique β subunits. That is, both hormones are dimeric glycoproteins and share a common α subunit. Their unique β subunits, however, derive from different genes encoding distinct proteins. Past and recent research indicates synthesis and release of the two hormones are subject to extensive and independent regulation. LH appears to be secreted predominantly via the regulated secretory pathway, whereas FSH release is largely constitutive. As such, investigations of FSH-β subunit synthesis may lend direct insight into mechanisms underlying patterns of secreted FSH, more so than investigations of the LHβ subunit. Here, we review recent investigations of transcriptional regulation of the FSH-β subunit gene from different mammalian species, including humans. The results reveal both conserved and species-specific regulatory mechanisms that might contribute to inter-species variation in FSH release.
Inhibins are gonadal hormones that suppress follicle-stimulating hormone (FSH) synthesis by pituitary gonadotrope cells. The structurally related activins stimulate FSH by signaling through complexes ...of type I and type II receptors. Two models of inhibin action were proposed in 2000. First, inhibins function as competitive receptor antagonists, binding activin type II receptors with high affinity in the presence of the TGF-β type III coreceptor, betaglycan. Second, immunoglobulin superfamily, member 1 (IGSF1, then called p120) was proposed to mediate inhibin B antagonism of activin signaling via its type I receptor. These ideas have been challenged over the past few years. Rather than playing a role in inhibin action, IGSF1 is involved in the central control of the thyroid gland. Betaglycan binds inhibin A and inhibin B with high affinity, but only functions as an obligate inhibin A coreceptor in murine gonadotropes. There is likely to be a distinct, but currently unidentified coreceptor for inhibin B.
Betaglycan binds inhibin A with higher affinity than inhibin B.Ablation of betaglycan in pituitary gonadotropes impairs inhibin A, but not inhibin B action in mice.Contrary to previous reports, IGSF1 is not an inhibin B coreceptor.Loss of function mutations in IGSF1 cause central hypothyroidism in humans and mice.There is an inhibin B coreceptor in the pituitary gland awaiting discovery.
Pituitary follicle-stimulating hormone (FSH) is an essential regulator of fertility in females and of quantitatively normal spermatogenesis in males. Pituitary-derived activins are thought to act as ...major stimulators of FSH synthesis by gonadotrope cells. In vitro, activins signal via SMAD3, SMAD4, and forkhead box L2 (FOXL2) to regulate transcription of the FSHβ subunit gene (Fshb). Consistent with this model, gonadotrope-specific Smad4 or Foxl2 knock-out mice have greatly reduced FSH and are subfertile. The role of SMAD3 in vivo is unresolved; however, residual FSH production in Smad4 conditional knock-out mice may derive from partial compensation by SMAD3 and its ability to bind DNA in the absence of SMAD4. To test this hypothesis and determine the role of SMAD3 in FSH biosynthesis, we generated mice lacking both the SMAD3 DNA binding domain and SMAD4 specifically in gonadotropes. Conditional knock-out females were hypogonadal, acyclic, and sterile and had thread-like uteri; their ovaries lacked antral follicles and corpora lutea. Knock-out males were fertile but had reduced testis weights and epididymal sperm counts. These phenotypes were consistent with those of Fshb knock-out mice. Indeed, pituitary Fshb mRNA levels were nearly undetectable in both male and female knock-outs. In contrast, gonadotropin-releasing hormone receptor mRNA levels were significantly elevated in knock-outs in both sexes. Interestingly, luteinizing hormone production was altered in a sex-specific fashion. Overall, our analyses demonstrate that SMAD3 is required for FSH synthesis in vivo.
Coronary heart disease damages the trabecular myocardium, and the regeneration of trabecular vessels may alleviate ischemic injury. However, the origins and developmental mechanisms of trabecular ...vessels remain unknown. Here, we show that murine ventricular endocardial cells generate trabecular vessels through an “angioEMT” mechanism. Time course fate mapping defined a specific wave of trabecular vascularization by ventricular endocardial cells. Single-cell transcriptomics and immunofluorescence identified a subpopulation of ventricular endocardial cells that underwent endocardial-mesenchymal transition (EMT) before these cells generated trabecular vessels. Ex vivo pharmacological activation and in vivo genetic inactivation experiments identified an EMT signal in ventricular endocardial cells involving SNAI2-TGFB2/TGFBR3, which was a prerequisite for later trabecular-vessel formation. Additional loss- and gain-of-function genetic studies showed that VEGFA-NOTCH1 signaling regulated post-EMT trabecular angiogenesis by ventricular endocardial cells. Our finding that trabecular vessels originate from ventricular endocardial cells through a two-step angioEMT mechanism could inform better regeneration medicine for coronary heart disease.
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•Trabecular coronary vessels arise from ventricular endocardial cells•Trabecular coronary vessels are formed by a two-step angioEMT mechanism•TGF-β signaling regulates the endocardial-coronary endothelial fate change via endocardial-mesenchymal transition•VEGFA-NOTCH1 signaling drives trabecular coronary-vessel formation by angiogenesis
Lu et al. identify two waves of coronary-vessel formation at trabecular and compact myocardium of the murine heart. Their work finds that trabecular vessels arise from ventricular endocardial cells and characterizes a two-step angioEMT mechanism underlying the process that may inform better regeneration medicine for coronary heart disease.
This study compared the relative efficacy of two strategies designed to mitigate psychological reactance in health campaigns by using reminders of behavioral autonomy: preemptive scripts, which ...appear before the appeal, and restoration postscripts, which appear after. Employing a mixed-model experiment with a 2 (threat to freedom: low vs. high) × 3 (reactance-mitigation strategy: control vs. preemptive script vs. restoration postscript) × 2 (health campaign topic: exercise vs. nutrition) between-subjects design and a within-subjects factor of time (immediate posttest measurement followed by a one-week delay), this study (N = 394) compared the effects of the two mitigation strategies on reactance, attitude, and behavioral intention at two points in time. Moderated mediation models indicated that the reactance-mitigation strategies equivalently reduced the degree to which reactance was experienced in response to increasingly threatening health appeals (relative to the control). This effect indirectly influenced behavioral intention via attitude change and remained after one week.
This study examined the influence of the social networking site Facebook and face-to-face support networks on depression among (N = 361) college students. The authors used the Relational Health ...Communication Competence Model as a framework for examining the influence of communication competence on social support network satisfaction and depression. Moreover, they examined the influence of interpersonal and social integrative motives as exogenous variables. On the basis of previous work, the authors propose and test a theoretical model using structural equation modeling. The results indicated empirical support for the model, with interpersonal motives predicting increased face-to-face and computer-mediated competence, increased social support satisfaction with face-to-face and Facebook support, and lower depression scores. The implications of the findings for theory, key limitations, and directions for future research are discussed.
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