The FGF2‐induced tanycyte proliferation involves a connexin 43 hemichannel/purinergic‐dependent pathway

• Published in: Journal of neurochemistry 2021-01, Vol.156 (2), p.182-199
• Main Authors: Recabal, Antonia, Fernández, Paola, López, Sergio, Barahona, María J., Ordenes, Patricio, Palma, Alejandra, Elizondo‐Vega, Roberto, Farkas, Carlos, Uribe, Amparo, Caprile, Teresa, Sáez, Juan C., García‐Robles, María A.
• Format: Article
• Language: English
• Subjects: Animals; ATP; Body weight; Bromodeoxyuridine; Calcium; Calcium (intracellular); Calcium ions; cell biology; Cell division; Cell Proliferation - physiology; Connexin 43; Connexin 43 - metabolism; Ependymoglial Cells - physiology; Fibroblast growth factor 2; Fibroblast Growth Factor 2 - metabolism; gliogenesis; Growth factors; Hypothalamus; Ion Channels - metabolism; Ion concentration; Male; Molecular modelling; Neural Stem Cells - physiology; Neurogenesis; Neurogenesis - physiology; Neuronal-glial interactions; Original; ORIGINAL ARTICLES; Purine P2Y receptors; purinergic receptors; Radial glial cells; Rats; Rats, Sprague-Dawley; Receptors; Signal Transduction - physiology; signal transductions; Tanycyte; Tanycytes; Ventricle; Ventricles (cerebral)
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.15188

In the adult hypothalamus, the neuronal precursor role is attributed to the radial glia‐like cells that line the third‐ventricle (3V) wall called tanycytes. Under nutritional cues, including hypercaloric diets, tanycytes proliferate and differentiate into mature neurons that moderate body weight, suggesting that hypothalamic neurogenesis is an adaptive mechanism in response to metabolic changes. Previous studies have shown that the tanycyte glucosensing mechanism depends on connexin‐43 hemichannels (Cx43 HCs), purine release, and increased intracellular free calcium ion concentration [(Ca2+)i] mediated by purinergic P2Y receptors. Since, Fibroblast Growth Factor 2 (FGF2) causes similar purinergic events in other cell types, we hypothesize that this pathway can be also activated by FGF2 in tanycytes to promote their proliferation. Here, we used bromodeoxyuridine (BrdU) incorporation to evaluate if FGF2‐induced tanycyte cell division is sensitive to Cx43 HC inhibition in vitro and in vivo. Immunocytochemical analyses showed that cultured tanycytes maintain the expression of in situ markers. After FGF2 exposure, tanycytic Cx43 HCs opened, enabling release of ATP to the extracellular milieu. Moreover, application of external ATP was enough to induce their cell division, which could be suppressed by Cx43 HC or P2Y1‐receptor inhibitors. Similarly, in vivo experiments performed on rats by continuous infusion of FGF2 and a Cx43 HC inhibitor into the 3V, demonstrated that FGF2‐induced β‐tanycyte proliferation is sensitive to Cx43 HC blockade. Thus, FGF2 induced Cx43 HC opening, triggered purinergic signaling, and increased β‐tanycytes proliferation, highlighting some of the molecular mechanisms involved in the cell division response of tanycyte. This article has an Editorial Highlight see https://doi.org/10.1111/jnc.15218. Fibroblast growth factor 2 (FGF2) accelerates basal‐tanycyte cell division, which is sensitive to Cx43 hemichannel inhibition in vitro and in vivo. In primary cultures of tanycyte, the mitogen FGF2 acts over FGF1R inducing Cx43 hemichannel opening and ATP release. Extracellular ATP induces tanycytic division through P2Y1 receptors. In vivo infusion of FGF2 with a Cx43 hemichannel inhibitor into the 3V showed less tanycytes in mitosis. These findings contribute to elucidate the molecular mechanisms involved in tanycyte proliferation. This article has an Editorial Highlight see https://doi.org/10.1111/jnc.15218.