Abstract
ABSTRACTIn most vertebrates, including zebrafish, the hypothalamic serotonergic cerebrospinal fluid-contacting (CSF-c) cells constitute a prominent population. In contrast to the hindbrain serotonergic neurons, little is known about the development and function of these cells. Here, we identify fibroblast growth factor (Fgf)3 as the main Fgf ligand controlling the ontogeny of serotonergic CSF-c cells. We show that fgf3 positively regulates the number of serotonergic CSF-c cells, as well as a subset of dopaminergic and neuroendocrine cells in the posterior hypothalamus via control of proliferation and cell survival. Further, expression of the ETS-domain transcription factor etv5b is downregulated after fgf3 impairment. Previous findings identified etv5b as critical for the proliferation of serotonergic progenitors in the hypothalamus, and therefore we now suggest that Fgf3 acts via etv5b during early development to ultimately control the number of mature serotonergic CSF-c cells. Moreover, our analysis of the developing hypothalamic transcriptome shows that the expression of fgf3 is upregulated upon fgf3 loss-of-function, suggesting activation of a self-compensatory mechanism. Together, these results highlight Fgf3 in a novel context as part of a signalling pathway of critical importance for hypothalamic development.
Highlights
Serotonin (5-hydroxytryptamine, 5-HT) is an ancient signalling molecule present in the nervous system of animals from cnidarian and bilaterian lineages (Hay-Schmidt, 2000; Kass-Simon and Pierobon, 2007; Moroz and Kohn, 2016; Stach, 2005)
Using three different approaches for genetic manipulation, we identify Fgf3 as the main fibroblast growth factor (Fgf) ligand critical for development of serotonergic as well as dopaminergic cerebrospinal fluid-contacting (CSF-c) cells and arginine vasopressin-expressing cells located in the posterior hypothalamus
We found that homozygous fgf3t24152 mutants, fgf3 morpholino and CRISPR/Cas9-injected embryos had reduced numbers of serotonergic cerebrospinal fluid (CSF)-c cells, but depending on the approach used the severity of the phenotype varied (Fig. 3)
Summary
Serotonin (5-hydroxytryptamine, 5-HT) is an ancient signalling molecule present in the nervous system of animals from cnidarian and bilaterian lineages (Hay-Schmidt, 2000; Kass-Simon and Pierobon, 2007; Moroz and Kohn, 2016; Stach, 2005). Observations argue for an early effect of fgf on progenitors later giving rise to mature monoaminergic cells To test for this possibility we analysed proliferation rate and cell death at 36 hpf in the posterior hypothalamus after impairment of fgf (Fig. 6, Table S3). RNA sequencing results of Fgf-signalling pathway genes revealed that 56 out of 62 selected genes (Table S4) are expressed in the hypothalamus of wild types and mutants at 3 and 7 dpf (Fig. 8D). This is supported by our observation that the number of proliferating cells is decreased in parallel with increased cell death after fgf impairment This is in line with our earlier finding that Fgf-signalling, via etv5b, influences the proliferation of hypothalamic serotonergic CSF-c progenitor cells (Bosco et al, 2013). This suggests that only minor compensatory mechanisms are at hand in the fgf3t24152 mutant and/ or that the truncated Fgf isoform resulting from the fgf3t24152 mutation is still, at least partly, functional
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