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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

Expression of Gli genes in the presumptive hypothalamus at E10.5. (A–R)In situ detection of Gli genes in the presumptive hypothalamus of E10.5 Gli2zfd/+ and Gli2zfd/zfd mouse embryos as indicated. For each gene, three levels are shown, from pituitary/infundibulum (top row) through mamillary region (bottom row). Black arrowheads in (A–C,M–O) show co-expression of Gli1 and Gli3 in the midline; red arrowheads in (D,E,P,Q) show downregulation of Gli1 and Gli3 in the Gli2zfd/zfd midline. Scale bars, 200 μm.
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Figure 3: Expression of Gli genes in the presumptive hypothalamus at E10.5. (A–R)In situ detection of Gli genes in the presumptive hypothalamus of E10.5 Gli2zfd/+ and Gli2zfd/zfd mouse embryos as indicated. For each gene, three levels are shown, from pituitary/infundibulum (top row) through mamillary region (bottom row). Black arrowheads in (A–C,M–O) show co-expression of Gli1 and Gli3 in the midline; red arrowheads in (D,E,P,Q) show downregulation of Gli1 and Gli3 in the Gli2zfd/zfd midline. Scale bars, 200 μm.

Mentions: Our purpose was to determine for each of the mouse hypothalamic regions which member of the Gli family performs the GliA and which one the GliR function, and which combinations of GliA and GliR specify these regions—in short, the hypothalamic Shh-Gli code. 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). Thus, the first requisite for our study was to ascertain a detailed spatial-temporal expression map for the three mammalian Gli genes and Shh in the developing hypothalamus of the mouse (Figures 2 and 3). Although inactivation of Gli1 does not result in an abnormal phenotype (Park et al., 2000; Bai et al., 2002), Gli1 expression is a readout for Shh signaling [see references in Lewis et al. (2001)] and for this reason it was important to analyze its expression domain too. It has been described that, in the mouse neural plate, expression of Gli genes is first detected at E7.5 (neural fold); in this early stage of Gli expression, Gli1 is expressed only in the midline of the neural fold, while Gli2 and Gli3 expression is widespread in the entire ectoderm (Hui et al., 1994) and Shh is expressed in the underlying mesoderm (non-neural Shh; Echelard et al., 1993).


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)

Expression of Gli genes in the presumptive hypothalamus at E10.5. (A–R)In situ detection of Gli genes in the presumptive hypothalamus of E10.5 Gli2zfd/+ and Gli2zfd/zfd mouse embryos as indicated. For each gene, three levels are shown, from pituitary/infundibulum (top row) through mamillary region (bottom row). Black arrowheads in (A–C,M–O) show co-expression of Gli1 and Gli3 in the midline; red arrowheads in (D,E,P,Q) show downregulation of Gli1 and Gli3 in the Gli2zfd/zfd midline. Scale bars, 200 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Expression of Gli genes in the presumptive hypothalamus at E10.5. (A–R)In situ detection of Gli genes in the presumptive hypothalamus of E10.5 Gli2zfd/+ and Gli2zfd/zfd mouse embryos as indicated. For each gene, three levels are shown, from pituitary/infundibulum (top row) through mamillary region (bottom row). Black arrowheads in (A–C,M–O) show co-expression of Gli1 and Gli3 in the midline; red arrowheads in (D,E,P,Q) show downregulation of Gli1 and Gli3 in the Gli2zfd/zfd midline. Scale bars, 200 μm.
Mentions: Our purpose was to determine for each of the mouse hypothalamic regions which member of the Gli family performs the GliA and which one the GliR function, and which combinations of GliA and GliR specify these regions—in short, the hypothalamic Shh-Gli code. 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). Thus, the first requisite for our study was to ascertain a detailed spatial-temporal expression map for the three mammalian Gli genes and Shh in the developing hypothalamus of the mouse (Figures 2 and 3). Although inactivation of Gli1 does not result in an abnormal phenotype (Park et al., 2000; Bai et al., 2002), Gli1 expression is a readout for Shh signaling [see references in Lewis et al. (2001)] and for this reason it was important to analyze its expression domain too. It has been described that, in the mouse neural plate, expression of Gli genes is first detected at E7.5 (neural fold); in this early stage of Gli expression, Gli1 is expressed only in the midline of the neural fold, while Gli2 and Gli3 expression is widespread in the entire ectoderm (Hui et al., 1994) and Shh is expressed in the underlying mesoderm (non-neural Shh; Echelard et al., 1993).

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