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

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 ß-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 ß-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 ß-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.

Characterisation of endogenous players in fibroblast growth factor-regulated functions of hypothalamic tanycytes and energy-balance nuclei.

The mammalian hypothalamus regulates key homeostatic and neuroendocrine functions ranging from circadian rhythm and energy balance to growth and reproductive cycles via the hypothalamic-pituitary and hypothalamic-thyroid axes. In addition to its neurones, tanycytes are taking centre stage in the short- and long-term augmentation and integration of diverse hypothalamic functions, although the genetic regulators and mediators of their involvement are poorly understood. Exogenous interventions have implicated fibroblast growth factor (FGF) signalling, although the focal point of the action of FGF and any role for putative endogenous players also remains elusive. We carried out a comprehensive high-resolution screen of FGF signalling pathway mediators and modifiers using a combination of in situ hybridisation, immunolabelling and transgenic reporter mice, aiming to map their spatial distribution in the adult hypothalamus. Our findings suggest that ß-tanycytes are the likely focal point of exogenous and endogenous action of FGF in the third ventricular wall, utilising FGF receptor (FGFR)1 and FGFR2 IIIc isoforms, but not FGFR3. Key IIIc-activating endogenous ligands include FGF1, 2, 9 and 18, which are expressed by a subset of ependymal and parenchymal cells. In the parenchymal compartment, FGFR1-3 show divergent patterns, with FGFR1 being predominant in neuronal nuclei and expression of FGFR3 being associated with glial cell function. Intracrine FGFs are also present, suggestive of multiple modes of FGF function. Our findings provide a testable framework for understanding the complex role of FGFs with respect to regulating the metabolic endocrine and neurogenic functions of hypothalamus in vivo.

Fgf10-expressing tanycytes add new neurons to the appetite/energy-balance regulating centers of the postnatal and adult hypothalamus.

Increasing evidence suggests that neurogenesis occurs in the postnatal and adult mammalian hypothalamus. However, the identity and location of the putative progenitor cells is under much debate, and little is known about the dynamics of neurogenesis in unchallenged brain. Previously, we postulated that Fibroblast growth factor 10-expressing (Fgf10(+)) tanycytes constitute a population of progenitor cells in the mouse hypothalamus. Here, we show that Fgf10(+) tanycytes express markers of neural stem/progenitor cells, divide late into postnatal life, and can generate both neurons and astrocytes in vivo. Stage-specific lineage-tracing of Fgf10(+) tanycytes using Fgf10-creERT2 mice, reveals robust neurogenesis at postnatal day 28 (P28), lasting as late as P60. Furthermore, we present evidence for amplification of Fgf10-lineage traced neural cells within the hypothalamic parenchyma itself. The neuronal descendants of Fgf10(+) tanycytes predominantly populate the arcuate nucleus, a subset of which express the orexigenic neuronal marker, Neuropeptide-Y, and respond to fasting and leptin-induced signaling. These studies provide direct evidence in support of hypothalamic neurogenesis during late postnatal and adult life, and identify Fgf10(+) tanycytes as a source of parenchymal neurons with putative roles in appetite and energy balance.