A neuroepithelial wave of BMP signalling drives anteroposterior specification of the tuberal hypothalamus

Abstract

The tuberal hypothalamus houses several major hypothalamic nuclei, dozens of transcriptionally distinct cell types, and clinically relevant cell populations implicated in obesity and related metabolic disorders. Building on recent advances in the field, here we draw upon transcriptional, signalling, and fate mapping analyses of chicken embryos and neuroepithelial explants to analyze tuberal hypothalamic development. We show that a wave of BMP signalling sweeps through early floor plate-like progenitors overlying prospective Rathkes pouch as they track anteriorly. The timing of BMP signalling correlates with cell fate, with anterior tuberal specification complete by Hamilton-Hamburger (HH) stage 10 but posterior tuberal progenitors requiring BMPs after this point. scRNA-Seq profiling of FGF10-expressing cells, a proxy for cells with active BMP signalling, through HH8-21 reveals transcriptional differences that may underlie their differing response to BMPs, and the switch from neuroepithelial progenitors to stem-like radial glial cells. This study provides an integrated account of the development of the tuberal hypothalamus.

Human embryonic tanycyte: heterogeneity and developmental trajectory

“…The exploration of embryonic tanycytes is limited by their difficulty to be set apart from neural pogenitors, here we managed a good separation between these two by mapping human embryonic data onto a mouse reference data where tanycyte were clearly characterised. We found that comparing to RAX+ neural progenitors (SHH+, occur mostly at early embryonic stages), tanycytes express more radial glial genes FABP7, astrocyte marker AQP4, GFAP as well as tanycyte markers DIO2, CRYM, FRZB (Figure 2), in consistent with their radial glia-like identity as well as their function (Chinnaiya et al 2022). Regarding human tanycyte heterogeneity, we identified similar tanycyte subtypes (α and β) to adult rodent tanycytes, though their gene expression profiles are slightly different that may reflect both species difference and/or functional maturity, for example, DIO2 and FGFR1 are more highly expressed in β tanycyte in adult mouse (Campbell et al 2017), but in human embryonic tanycyte, they are similarly expressed in both α and β tanycytes (Figures 3 & S3).…”

“…Differentially expressed gene analysis shows that tanycyte marker genes CRYM, MT2A and FRZB (Campbell et al 2017) were unregulated in embryonic tanycytes, while anterior tuberal hypothalamus progenitor markers HES5 and SHH (Chinnaiya et al 2022) were upregulated in the neural progenitor clusters (Figure 2_A, Table S2). Apart from that, astrocyte markers SLC1A3/GLAST, FABP7/BLBP, GFAP, AQP4 and S100B were also expressed more in the tanycyte clusters comparing to the neural progenitor clusters (Figures 2 and 3_B).…”

“…NNAT plays a role in metabolic regulation and it has been shown to be expressed by tanycyte not by neurons in the arcuate nucleus (Vrang et al 2010), FABP7 is a radial glia marker (De Rosa et al 2012). The upregulation of both genes may reflect the transition from a progenitor state towards a radial glia-like tanycyte fate (Chinnaiya et al 2022). The uplift of FABP7 is first followed by the rise of CLU and APOE , then by the increased expression of a marker gene CRYM shared by both α and β tanycytes (Campbell et al 2017).…”

“…Regarding the developmental trajectory of tanycytes, Chinnaiya et al (2022) have identified a tuberal hypothalamus progenitor population that shares very similar gene expression profile with adult rodent tanycytes: they both express RAX, VIM and FGF10. Chinnaiya et al (2022) collected single cell transcriptomics data for those cells from a chicken dataset (Kim et al 2022) and compared them between different embryonic stages, they found that as development moved forward, radial glia markers VIM and FABP7 got upregulated in embryonic tanycyte cells, likely reflecting a transition from neural progenitors towards radial glia-like tanycytes (Chinnaiya et al 2022). However, how this developmental process looks like in human still remains to be discovered.…”