Fibroblast growth factor 10 is a negative regulator of postnatal neurogenesis in the mouse hypothalamus

Abstract

New neurons are generated in the postnatal rodent hypothalamus, with a subset of tanycytes in the third ventricular (3V) wall serving as neural stem/progenitor cells. However, the precise stem cell niche organization, the intermediate steps and the endogenous regulators of postnatal hypothalamic neurogenesis remain elusive. Quantitative lineage-tracing in vivo revealed that conditional deletion of fibroblast growth factor 10 (Fgf10) from Fgf10-expressing β-tanycytes at postnatal days (P)4-5 results in the generation of significantly more parenchymal cells by P28, composed mostly of ventromedial and dorsomedial neurons and some glial cells, which persist into adulthood. A closer scrutiny in vivo and ex vivo revealed that the 3V wall is not static and is amenable to cell movements. Furthermore, normally β-tanycytes give rise to parenchymal cells via an intermediate population of α-tanycytes with transient amplifying cell characteristics. Loss of Fgf10 temporarily attenuates the amplification of β-tanycytes but also appears to delay the exit of their α-tanycyte descendants from the germinal 3V wall. Our findings suggest that transience of cells through the α-tanycyte domain is a key feature, and Fgf10 is a negative regulator of postnatal hypothalamic neurogenesis.

Control of neurogenic competence in mammalian hypothalamic tanycytes

“…While tanycyte-derived newborn neurons may play a role in regulating a range of behaviors ( 3 , 7 , 8 ), levels of postnatal tanycyte-derived neurogenesis are low and virtually undetectable in adulthood ( 9 ). As a result, little is known about the molecular identity or connectivity of tanycyte-derived neurons (TDNs) ( 6 , 9 ). A better understanding of the gene regulatory networks that control neurogenic competence in hypothalamic tanycytes would both give insight into the function of TDNs and potentially identify new therapeutic approaches for modulation and repair of hypothalamic neural circuitry.…”

“…Tanycytes are subdivided into alpha1, alpha2, beta1, and beta2 subtypes based on dorsoventral position and marker gene expression and closely resemble neural progenitors in morphology and gene expression profile. Tanycytes have been reported to generate small numbers of neurons and glia in the postnatal period, although at much lower levels than in more extensively characterized sites of ongoing neurogenesis, such as the subventricular zone of the lateral ventricles or the subgranular zone of the dentate gyrus (3)(4)(5)(6). While tanycytederived newborn neurons may play a role in regulating a range of behaviors (3,7,8), levels of postnatal tanycyte-derived neurogenesis are low and virtually undetectable in adulthood (9).…”

Control of neurogenic competence in mammalian hypothalamic tanycytes

“…While tanycyte-derived newborn neurons may play a role in regulating a range of behaviors ( 3 , 7 , 8 ), levels of postnatal tanycyte-derived neurogenesis are low and virtually undetectable in adulthood. Furthermore, little is known about the molecular identity or connectivity of tanycyte-derived neurons ( 6, 9 ). A better understanding of the gene regulatory networks that control neurogenic competence in hypothalamic tanycytes would both give insight into the function of tanycyte-derived neurons and potentially identify new therapeutic approaches for modulation and repair of hypothalamic neural circuitry.…”

“…Tanycytes are subdivided into alpha1, alpha2, beta1 and beta2 subtypes based on dorso-ventral position, morphology and gene expression profile, and closely resemble neural progenitors in morphology and gene expression profile. Tanycytes have been reported to generate small numbers of neurons and glia in the postnatal period, although at much lower levels than in more extensively characterized sites of ongoing neurogenesis such as the subventricular zone of the lateral ventricles or the subgranular zone of the dentate gyrus (3)(4)(5)(6). While tanycyte-derived newborn neurons may play a role in regulating a range of behaviors (3,7,8), levels of postnatal tanycyte-derived neurogenesis are low and virtually undetectable in adulthood.…”

Adult-born proopiomelanocortin neurons derived from Rax-expressing precursors mitigate the metabolic effects of congenital hypothalamic proopiomelanocortin deficiency

“…Although previous studies identified Rax as a tanycyte marker [ [18] , [19] , [20] ], we found that Rax is also expressed in a small population of parenchymal cells. While a subset of these cells had tanycyte-like morphology and probably represents tanycytes that migrated into the parenchyma before differentiation [ 31 , 40 ], the majority represented a different cell type that we termed “frizzy cells”, which were located primarily in the caudal Arc. Rax- negative frizzy cells expressing tdTomato were more broadly distributed, suggesting that frizzy cells move over long distances and downregulate Rax while migrating.…”