Brain atlas for glycoprotein hormone receptors at single-transcript level

Abstract

There is increasing evidence that anterior pituitary hormones, traditionally thought to have unitary functions in regulating single endocrine targets, act on multiple somatic tissues, such as bone, fat, and liver. There is also emerging evidence for anterior pituitary hormone action on brain receptors in mediating central neural and peripheral somatic functions. Here, we have created the most comprehensive neuroanatomical atlas on the expression of TSHR, LHCGR and FSHR. We have used RNAscope, a technology that allows the detection of mRNA at single-transcript level, together with protein level validation, to document Tshr expression in 173 and Fshr expression in 353 brain regions, nuclei and sub-nuclei identified using the Atlas for the Mouse Brain in Stereotaxic Coordinates. We also identified Lhcgr transcripts in 401 brain regions, nuclei and sub-nuclei. Complementarily, we used ViewRNA, another single-transcript detection technology, to establish the expression of FSHR in human brain samples, where transcripts were co-localized in MALAT1 positive neurons. In addition, we show high expression for all three receptors in the ventricular region-with yet unknown functions. Intriguingly, Tshr and Fshr expression in the ependymal layer of the third ventricle was similar to that of the thyroid follicular cells and testicular Sertoli cells, respectively. In contrast, Fshr was localized to NeuN-positive neurons in the granular layer of the dentate gyrus in murine and human brain-both are Alzheimer's disease vulnerable regions. Our atlas thus provides a vital resource for scientists to explore the link between the stimulation or inactivation of brain glycoprotein hormone receptors on somatic function. New actionable pathways for human disease may be unmasked through further studies.

Emerging roles of brain tanycytes in regulating blood–hypothalamus barrier plasticity and energy homeostasis

“…Notably, the highest Fshr density was also found in the 3V tanycytes, which was not surprising, given its anatomical proximity to the anterior pituitary gland where FSH is synthesized in response to the hypothalamic gonadotropin‐releasing hormone GnRH. Likewise, tanycytes also expressed the LHCGR, 15 although at a much lower transcript number or density (Figure 2). Finally, we also recently documented the expression of oxytocin receptors in 3V tanycytes.…”

“…Utilizing RNAscope, we recently reported the expression of another glycoprotein hormone receptor, FSHR, in multiple brain sites 15,77 . Notably, the highest Fshr density was also found in the 3V tanycytes, which was not surprising, given its anatomical proximity to the anterior pituitary gland where FSH is synthesized in response to the hypothalamic gonadotropin‐releasing hormone GnRH.…”

“…Increasing evidence suggests that anterior pituitary glycoprotein hormones, traditionally considered to have unitary functions in targeting single endocrine sites, act on multiple somatic tissues 74–77 . Furthermore, in light of emerging evidence for anterior pituitary hormone action on brain receptors in regulating central neural and peripheral somatic functions, 77 we have recently discovered additional multiple brain sites expressing TSHRs 15 . Tanycytes of the 3V not only possess the highest number of Tshr transcripts, but also display the highest transcript density 15 (Figures 2 and 3).…”

“…Given our recent discovery of a broad array of anterior pituitary hormone receptors, notably TSHRs, follicle‐stimulating hormone receptors (FSHRs), and luteinizing hormone receptors (LHCGRs), in multiple brain sites, 15 our perspective will focus on the question—what is the role of ependymal TSHRs in mediating blood–hypothalamus barrier (BHB) plasticity in relation to ingestive behavior and energy homeostasis? While little is known about this topic, the main functions and neuroanatomy of the BHB are well known.…”

“…14 However, the first mention of tanycytic TSHR expression, to our knowledge, was 15 years earlier by the Hazlerigg laboratory, describing strong expression of TSHRs both within the PT itself and in adjacent cells in the median eminence (ME), extending into the ependymal paraventricular region surrounding the base of the third ventricle in sheep. 2 Given our recent discovery of a broad array of anterior pituitary hormone receptors, notably TSHRs, follicle-stimulating hormone receptors (FSHRs), and luteinizing hormone receptors (LHCGRs), in multiple brain sites, 15 our perspective will focus on the questionwhat is the role of ependymal TSHRs in mediating blood-hypothalamus barrier (BHB) plasticity in relation to ingestive behavior and energy homeostasis? While little is known about this topic, the main functions and neuroanatomy of the BHB are well known.…”