ESPE Yearbook of Paediatric Endocrinology

Front Endocrinol (Lausanne). 2022 Mar 16;13:869019. doi: 10.3389/fendo.2022.869019. PMID: 35370973. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8966543/

Brief Summary: This mouse study explores the function of alpha-tanycytes, which are neurogenic stem cells located in the medio-basal hypothalamus and expressing GFAP. GFAP-cell deficiency leads to hypogonadotropic hypogonadism, demonstrating the role of tanycytes in the regulation of reproduction.

A neurogenic niche was recently identified in the medio-basal hypothalamus of humans, rodents and sheep [1], [2]. Radial glia-like cells lining the ventricular wall, namely tanycytes, were identified as the neural stem/progenitor cells (NSPCs) in this region [3]–[5] and express glial fibrillar acid protein (GFAP) [6], [7].

This study investigated the role of GFAP-positive tanycytes in physiological functions controlled by the hypothalamus. To explore the role of adult GFAP-expressing tanycytes in hypothalamic function, the authors used transgenic mice expressing Herpes Simplex Virus-Thymidine kinase under the control of the GFAP promoter and subjected them to intra-cerebroventricular infusion of Ganciclovir (GCV), that selectively eliminated GFAP-positive dividing cells. In vitro, this depletion markedly decreased the neurospherogenic capacities of this region, indicating that elimination of alpha-tanycytes completely halted cell proliferation. In vivo, suppression of GFAP-expressing tanycytes had no effect on body weight or food intake, while decreased testes weights and drastically reduced testosterone secretion by Leydig cells, associated with decreased circulating LH levels. This pattern is suggestive of hypogonadotropic hypogonadism, which was consistent with decreased GnRH immunoreactivity both in the pre-optic area and in the median eminence. Although Ganciclovir exposure itself is harmful to the testicle [8], [9], it generally occurs at higher doses and was not observed in the control group.

The existence of this neural stem cell niche indicates the presence of hypothalamic neuronal regeneration, that seems to control reproductive function and, as described in other studies, food intake [3]. This could have an important clinical implication and further studies will be needed to evaluate the possible role of these stem cells in the treatment of hypothalamic disease.

References: 1. Sharif A, Fitzsimons CP, Lucassen PJ. (2021) “Neurogenesis in the adult hypothalamus: A distinct form of structural plasticity involved in metabolic and circadian regulation, with potential relevance for human pathophysiology.” Handb Clin Neurol.; 179:125–140. 2. Yoo S, Blackshaw S. (2018) “Regulation and function of neurogenesis in the adult mammalian hypothalamus.” Prog Neurobiol.; 170:53–66. 3. Li J, Tang Y, Cai D. (2012) “IKKβ/NF-κB disrupts adult hypothalamic neural stem cells to mediate a neurodegenerative mechanism of dietary obesity and pre-diabetes.” Nat Cell Biol.; 14(10):999–1012. 4. Lee DA, Bedont JL, Pak T, Wang H, Song J, Miranda-Angulo A, Takiar V, Charubhumi V, Balordi F, Takebayashi H, Aja S, Ford E, Fishell G, Blackshaw S. (2012) “Tanycytes of the hypothalamic median eminence form a diet-responsive neurogenic niche.” Nat Neurosci.; 15(5):700–2. 5. Robins SC, Stewart I, McNay DE, Taylor V, Giachino C, Goetz M, Ninkovic J, Briancon N, Maratos-Flier E, Flier JS, Kokoeva MV, Placzek M. (2013) “α-Tanycytes of the adult hypothalamic third ventricle include distinct populations of FGF-responsive neural progenitors.” Nat Commun.; 4:2049. 6. Chaker Z, George C, Petrovska M, Caron JB, Lacube P, Caillé I, Holzenberger M. (2016) “Hypothalamic neurogenesis persists in the aging brain and is controlled by energy-sensing IGF-I pathway.” Neurobiol Aging.; 41:64–72. 7. Campbell JN, Macosko EZ, Fenselau H, Pers TH, Lyubetskaya A, Tenen D, Goldman M, Verstegen AM, Resch JM, McCarroll SA, Rosen ED, Lowell BB, Tsai LT. (2017) “A molecular census of arcuate hypothalamus and median eminence cell types.” Nat Neurosci.; 20(3):484–496. 8. Faqi AS, Klug A, Merker HJ, Chahoud I. (1997) “Ganciclovir induces reproductive hazards in male rats after short-term exposure.” Hum Exp Toxicol.; 16(9):505–11. 9. Nihi F, Moreira D, Santos Lourenço AC, Gomes C, Araujo SL, Zaia RM, Trevisani NB, de Athayde Pinto L, Moura-Costa DD, de Morais RN, Roma Paumgartten FJ, Martino-Andrade AJ. (2014) “Testicular effects following in utero exposure to the antivirals acyclovir and ganciclovir in rats.” Toxicol Sci.; 139(1):220–33.