Abstract
In the developing brain, growth and differentiation are intimately linked. Here, we show that in the zebrafish embryo, the homeodomain transcription factor Rx3 coordinates these processes to build the tuberal/anterior hypothalamus. Analysis of rx3 chk mutant/rx3 morphant fish and EdU pulse-chase studies reveal that rx3 is required to select tuberal/anterior hypothalamic progenitors and to orchestrate their anisotropic growth. In the absence of Rx3 function, progenitors accumulate in the third ventricular wall, die or are inappropriately specified, the shh+ anterior recess does not form, and its resident pomc+, ff1b+ and otpb+ Th1+ cells fail to differentiate. Manipulation of Shh signalling shows that Shh coordinates progenitor cell selection and behaviour by acting as an on-off switch for rx3. Together, our studies show that Shh and Rx3 govern formation of a distinct progenitor domain that elaborates patterning through its anisotropic growth and differentiation.
Highlights
The hypothalamus is an ancient part of the ventral forebrain
Our studies show that Shh and Rx3 govern formation of a distinct progenitor domain that elaborates patterning through its anisotropic growth and differentiation
Here, we show that Rx3 function is required for morphogenesis of the tuberal/anterior hypothalamus and governs three aspects of cell behaviour: it re-specifies progenitor types to tuberal/anterior identities, promotes their survival and governs their anisotropic growth/migration
Summary
The hypothalamus is an ancient part of the ventral forebrain. It centrally regulates homeostatic processes that are essential to survival and species propagation, including autonomic regulation of energy balance, growth, stress and reproduction. Increased rx expression was accompanied by changes that appeared to phenocopy loss of rx, notably a significant decrease in tuberal/ anterior territory (Fig. 7D,J white lines and red arrows), a decrease in hypothalamic pomc+ cells (Fig. 7E,K,M), the loss of ff1b expression (Fig. 7F,L), a decrease in Th1+ Group2/3 neurons (Fig. S5E,F; note Groups 4-6 in the posterior hypothalamus are unaffected) and a failure to downregulate sox in zone II (not shown). These observations suggest that Shh mediates rx downregulation in zone II, and that this is essential for differentiation of tuberal/anterior hypothalamic progenitors. These results suggest that a Shh-rx ON and Shhrx OFF feedback loop (Fig. 7Z) is essential for the development of the tuberal/anterior hypothalamus
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