Abstract
Secreted protein Sonic hedgehog (Shh) ventralizes the neural tube by modulating the crucial balance between activating and repressing functions (GliA, GliR) of transcription factors Gli2 and Gli3. This balance—the Shh-Gli code—is species- and context-dependent and has been elucidated for the mouse spinal cord. The hypothalamus, a forebrain region regulating vital functions like homeostasis and hormone secretion, shows dynamic and intricate Shh expression as well as complex regional differentiation. Here we asked if particular combinations of Gli2 and Gli3 and of GliA and GliR functions contribute to the variety of hypothalamic regions, i.e., we wanted to approach the question of a possible hypothalamic version of the Shh-Gli code. Based on mouse mutant analysis, we show that: (1) hypothalamic regional heterogeneity is based in part on differentially stringent requirements for Gli2 or Gli3; (2) another source of diversity are differential requirements for Shh of neural vs. non-neural origin; (3) the medial progenitor domain known to depend on Gli2 for its development generates several essential hypothalamic nuclei plus the pituitary and median eminence; (4) the suppression of Gli3R by neural and non-neural Shh is essential for hypothalamic specification. Finally, we have mapped our results on a recent model which considers the hypothalamus as a transverse region with alar and basal portions. Our data confirm the model and are explained by it.
Highlights
Sonic hedgehog (Shh) is a morphogen required for ventral neural tube specification (Echelard et al, 1993; Ericson et al, 1995, 1997; Chiang et al, 1996)
10 μm paraffin sections were analyzed under a confocal microscope (LSM700 -Zeiss) and DAPI and bromo-2 -deoxyuridine (BrdU)-positive cells were counted in 100-μm-wide bins encompassing the thickness of the neuroepithelium at four hypothalamic sites on two histological sections per level in three animals per age and genotype (WT, Gli2zfd/zfd, Gli3Xt−J/Xt−J, and Foxb1-Cre;Shhf /+;Gli3Xt−J/+ double mutants)
The expression of Gli1, Gli3, and Shh has been assessed at several stages in the developing chick hypothalamus, but in mouse the data are less comprehensive (Aoto et al, 2002; Ohyama et al, 2008)
Summary
Sonic hedgehog (Shh) is a morphogen required for ventral neural tube specification (Echelard et al, 1993; Ericson et al, 1995, 1997; Chiang et al, 1996). Shh acts through the Gli transcriptional activators (GliAs) and repressors (GliRs); the balance between GliA and GliR specifies ventral differentiation and proliferation (Lee et al, 1997; Ruiz i Altaba, 1997; Brewster et al, 1998) This “Shh-Gli code” is known for the mouse spinal cord [reviewed in Ruiz i Altaba et al (2003), Dessaud et al (2008), Ingham et al (2011)] and brainstem (Wang et al, 1995; Blaess et al, 2006, 2011; Feijoo et al, 2011). Neither Gli nor Gli are required for overall patterning of the alar hypothalamus and preoptic area These data confirm the main tenets of the model (Puelles et al, 2012), since they strongly support a subdivision of the developing hypothalamus into alar and basal domains
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