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Differential requirements for Gli2 and Gli3 in the regional specification of the mouse hypothalamus.

Haddad-Tóvolli R, Paul FA, Zhang Y, Zhou X, Theil T, Puelles L, Blaess S, Alvarez-Bolado G - Front Neuroanat (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Cell Biology and Neuroanatomy, University of Heidelberg Heidelberg, Germany.

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.

No MeSH data available.


Related in: MedlinePlus

Either Gli2A or Gli3A is sufficient for the specification of the preoptic region and alar hypothalamus. (A–D)In situ detection of preoptic marker gene Nkx2.1 on E18.5 mouse brain sections, genotypes as indicated. Black arrowheads, preoptic neuronal nuclei; white arrowheads, additional telencephalic expression domains. (E–L)In situ detection of anterior marker genes on E18.5 mouse brain sections, markers and genotypes as indicated. Arrowheads in E–H indicate the supraoptic and paraventricular nuclei; arrows in I–L indicate the suprachiasmatic nucleus. Scale bars 500 μm.
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Figure 4: Either Gli2A or Gli3A is sufficient for the specification of the preoptic region and alar hypothalamus. (A–D)In situ detection of preoptic marker gene Nkx2.1 on E18.5 mouse brain sections, genotypes as indicated. Black arrowheads, preoptic neuronal nuclei; white arrowheads, additional telencephalic expression domains. (E–L)In situ detection of anterior marker genes on E18.5 mouse brain sections, markers and genotypes as indicated. Arrowheads in E–H indicate the supraoptic and paraventricular nuclei; arrows in I–L indicate the suprachiasmatic nucleus. Scale bars 500 μm.

Mentions: Sonic hedgehog is required to specify hypothalamic structures and the preoptic area (Chiang et al., 1996; Pabst et al., 2000; Rallu et al., 2002). In mouse mutants lacking Shh expression in the neural tube (Foxb1-Cre;Shhf/f mutants), however, the preoptic and alar hypothalamus have only a moderate phenotype, mostly evident in their reduced size (Szabo et al., 2009a; Zhao et al., 2012), indicating that they are specified by Shh of non-neural origin (e.g., from the prechordal plate or the notochord). Here we asked what is the role of Gli factors in those two hypothalamic regions by analyzing mutants in which Gli2, Gli3 or both neural Shh and Gli3 were inactivated. Expression of transcription factor Nkx2-1, an early preoptic marker (Shimamura et al., 1995; Xu et al., 2008), was preserved in the Gli2zfd/zfd and Gli3Xt-J/Xt-J mutants (black arrowheads in Figures 4A–C).Incidentally, some non-preoptic telencephalic expression domains were missing in the mutants (white arrowheads in Figures 4A–D). Arginin-Vasopressin (Avp) is specifically expressed by the supraoptic and paraventricular nuclei (Swanson and Sawchenko, 1983) and shows robust expression in both mutants (Figures 4E–G). The transcription factor gene Lhx1 is a marker of the suprachiasmatic nucleus (Szabo et al., 2009a), and this pattern remains essentially unchanged in the mutants (Figures 4I–K). Finally, analysis of double Foxb1-Cre;Shhf/f;Gli3Xt-J/Xt-J mutants (lacking both neural Shh and Gli3) showed robust marker expression (Figures 4D,H,L).


Differential requirements for Gli2 and Gli3 in the regional specification of the mouse hypothalamus.

Haddad-Tóvolli R, Paul FA, Zhang Y, Zhou X, Theil T, Puelles L, Blaess S, Alvarez-Bolado G - Front Neuroanat (2015)

Either Gli2A or Gli3A is sufficient for the specification of the preoptic region and alar hypothalamus. (A–D)In situ detection of preoptic marker gene Nkx2.1 on E18.5 mouse brain sections, genotypes as indicated. Black arrowheads, preoptic neuronal nuclei; white arrowheads, additional telencephalic expression domains. (E–L)In situ detection of anterior marker genes on E18.5 mouse brain sections, markers and genotypes as indicated. Arrowheads in E–H indicate the supraoptic and paraventricular nuclei; arrows in I–L indicate the suprachiasmatic nucleus. Scale bars 500 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4373379&req=5

Figure 4: Either Gli2A or Gli3A is sufficient for the specification of the preoptic region and alar hypothalamus. (A–D)In situ detection of preoptic marker gene Nkx2.1 on E18.5 mouse brain sections, genotypes as indicated. Black arrowheads, preoptic neuronal nuclei; white arrowheads, additional telencephalic expression domains. (E–L)In situ detection of anterior marker genes on E18.5 mouse brain sections, markers and genotypes as indicated. Arrowheads in E–H indicate the supraoptic and paraventricular nuclei; arrows in I–L indicate the suprachiasmatic nucleus. Scale bars 500 μm.
Mentions: Sonic hedgehog is required to specify hypothalamic structures and the preoptic area (Chiang et al., 1996; Pabst et al., 2000; Rallu et al., 2002). In mouse mutants lacking Shh expression in the neural tube (Foxb1-Cre;Shhf/f mutants), however, the preoptic and alar hypothalamus have only a moderate phenotype, mostly evident in their reduced size (Szabo et al., 2009a; Zhao et al., 2012), indicating that they are specified by Shh of non-neural origin (e.g., from the prechordal plate or the notochord). Here we asked what is the role of Gli factors in those two hypothalamic regions by analyzing mutants in which Gli2, Gli3 or both neural Shh and Gli3 were inactivated. Expression of transcription factor Nkx2-1, an early preoptic marker (Shimamura et al., 1995; Xu et al., 2008), was preserved in the Gli2zfd/zfd and Gli3Xt-J/Xt-J mutants (black arrowheads in Figures 4A–C).Incidentally, some non-preoptic telencephalic expression domains were missing in the mutants (white arrowheads in Figures 4A–D). Arginin-Vasopressin (Avp) is specifically expressed by the supraoptic and paraventricular nuclei (Swanson and Sawchenko, 1983) and shows robust expression in both mutants (Figures 4E–G). The transcription factor gene Lhx1 is a marker of the suprachiasmatic nucleus (Szabo et al., 2009a), and this pattern remains essentially unchanged in the mutants (Figures 4I–K). Finally, analysis of double Foxb1-Cre;Shhf/f;Gli3Xt-J/Xt-J mutants (lacking both neural Shh and Gli3) showed robust marker expression (Figures 4D,H,L).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Cell Biology and Neuroanatomy, University of Heidelberg Heidelberg, Germany.

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.

No MeSH data available.


Related in: MedlinePlus