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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

Arcuate and ventromedial nuclei reduced, mamillary nucleus absent in the Gli2zfd/zfd mutant.In situ detection of tuberal markers (A–H) and mamillary markers (I–N) on sections of E18.5 WT and Gli2zfd/zfd mouse brains as indicated. Arrowheads in (G,H) indicate the lateral portion of the ventromedial nucleus; Arc, arcuate nucleus; MBO, mamillary nucleus; VMH, ventromedial nucleus. Scale bars, 500 μm. (O) The proposed hypothalamic model (see Figure 1B) showing in black the area affected by the Gli2  mutation. Black arrows indicate the arcuate nucleus (A–D) or the ventromedial nucleus (E,F,H). Dashed circles in (B,D,E–G,I,K,M) outline hypothalamic nuclei (as indicated).
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Figure 7: Arcuate and ventromedial nuclei reduced, mamillary nucleus absent in the Gli2zfd/zfd mutant.In situ detection of tuberal markers (A–H) and mamillary markers (I–N) on sections of E18.5 WT and Gli2zfd/zfd mouse brains as indicated. Arrowheads in (G,H) indicate the lateral portion of the ventromedial nucleus; Arc, arcuate nucleus; MBO, mamillary nucleus; VMH, ventromedial nucleus. Scale bars, 500 μm. (O) The proposed hypothalamic model (see Figure 1B) showing in black the area affected by the Gli2 mutation. Black arrows indicate the arcuate nucleus (A–D) or the ventromedial nucleus (E,F,H). Dashed circles in (B,D,E–G,I,K,M) outline hypothalamic nuclei (as indicated).

Mentions: We next analyzed the differentiation of the tuberal and mamillary regions in Gli2zfd/zfd brains at E18.5 (at this stage, characteristic neuronal nuclei are recognizable in the wildtype). Npy-expressing and Pomc-expressing neurons are specifically present in the arcuate nucleus (tuberal region; Elias et al., 1998; Figures 7A,C). In the Gli2zfd/zfd brain, the arcuate nuclei were not preserved as two distinct left and right domains. Instead, one single specifically labeled area was observed, unpaired and medial, sitting in the midline at the level of the tuberal area (dashed circle in Figures 7B,D). The third ventricle was abnormally absent at the site of this unpaired structure. Expression of SF-1 (nuclear receptor Nr5a1) specifically labels the ventromedial nucleus of the hypothalamus (Ikeda et al., 1995; Figure 7E). In the Gli2zfd/zfd brain, SF-1 was expressed in a median, unpaired group of cells (dashed circle in Figure 7F). The transcription factor Nkx2-1 is specifically expressed in the lateral part of the wildtype ventromedial nucleus (Nakamura et al., 2001; Figure 7G), but formed one single medial domain in the Gli2zfd/zfd brain (Figure 7H). The transcription factor genes Lhx1, Otp, and Sim1 are specifically expressed in the mamillary body (mamillary region) in the wildtype (Szabo et al., 2009a) but this expression was completely lost in the Gli2zfd/zfd mutant (Figures 7I–N). Together with the observations shown in Figures 5 and 6, these results indicate that Gli2 is essential for the specification of the medial progenitor domain (Alvarez-Bolado et al., 2012) of the basal hypothalamus. The Gli2zfd/zfd mutant mice showed an altered latero-medial organization of the molecular pattern of the basal hypothalamus consistent with a loss of the medial markers (notably reduced Six3 and loss of Tbx2, Otp, Sim1, and Lhx1) and derivatives (median eminence and neurohypophysis, mamillary body). The latter were substituted at the mutant midline by markers and derivatives typical of the lateral domain at this age, like Nkx2.1, Npy, Pomc, and SF-1. That the neurohypophysis is a derivative from this region has been described before (Pearson et al., 2011; Pearson and Placzek, 2013).


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)

Arcuate and ventromedial nuclei reduced, mamillary nucleus absent in the Gli2zfd/zfd mutant.In situ detection of tuberal markers (A–H) and mamillary markers (I–N) on sections of E18.5 WT and Gli2zfd/zfd mouse brains as indicated. Arrowheads in (G,H) indicate the lateral portion of the ventromedial nucleus; Arc, arcuate nucleus; MBO, mamillary nucleus; VMH, ventromedial nucleus. Scale bars, 500 μm. (O) The proposed hypothalamic model (see Figure 1B) showing in black the area affected by the Gli2  mutation. Black arrows indicate the arcuate nucleus (A–D) or the ventromedial nucleus (E,F,H). Dashed circles in (B,D,E–G,I,K,M) outline hypothalamic nuclei (as indicated).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 7: Arcuate and ventromedial nuclei reduced, mamillary nucleus absent in the Gli2zfd/zfd mutant.In situ detection of tuberal markers (A–H) and mamillary markers (I–N) on sections of E18.5 WT and Gli2zfd/zfd mouse brains as indicated. Arrowheads in (G,H) indicate the lateral portion of the ventromedial nucleus; Arc, arcuate nucleus; MBO, mamillary nucleus; VMH, ventromedial nucleus. Scale bars, 500 μm. (O) The proposed hypothalamic model (see Figure 1B) showing in black the area affected by the Gli2 mutation. Black arrows indicate the arcuate nucleus (A–D) or the ventromedial nucleus (E,F,H). Dashed circles in (B,D,E–G,I,K,M) outline hypothalamic nuclei (as indicated).
Mentions: We next analyzed the differentiation of the tuberal and mamillary regions in Gli2zfd/zfd brains at E18.5 (at this stage, characteristic neuronal nuclei are recognizable in the wildtype). Npy-expressing and Pomc-expressing neurons are specifically present in the arcuate nucleus (tuberal region; Elias et al., 1998; Figures 7A,C). In the Gli2zfd/zfd brain, the arcuate nuclei were not preserved as two distinct left and right domains. Instead, one single specifically labeled area was observed, unpaired and medial, sitting in the midline at the level of the tuberal area (dashed circle in Figures 7B,D). The third ventricle was abnormally absent at the site of this unpaired structure. Expression of SF-1 (nuclear receptor Nr5a1) specifically labels the ventromedial nucleus of the hypothalamus (Ikeda et al., 1995; Figure 7E). In the Gli2zfd/zfd brain, SF-1 was expressed in a median, unpaired group of cells (dashed circle in Figure 7F). The transcription factor Nkx2-1 is specifically expressed in the lateral part of the wildtype ventromedial nucleus (Nakamura et al., 2001; Figure 7G), but formed one single medial domain in the Gli2zfd/zfd brain (Figure 7H). The transcription factor genes Lhx1, Otp, and Sim1 are specifically expressed in the mamillary body (mamillary region) in the wildtype (Szabo et al., 2009a) but this expression was completely lost in the Gli2zfd/zfd mutant (Figures 7I–N). Together with the observations shown in Figures 5 and 6, these results indicate that Gli2 is essential for the specification of the medial progenitor domain (Alvarez-Bolado et al., 2012) of the basal hypothalamus. The Gli2zfd/zfd mutant mice showed an altered latero-medial organization of the molecular pattern of the basal hypothalamus consistent with a loss of the medial markers (notably reduced Six3 and loss of Tbx2, Otp, Sim1, and Lhx1) and derivatives (median eminence and neurohypophysis, mamillary body). The latter were substituted at the mutant midline by markers and derivatives typical of the lateral domain at this age, like Nkx2.1, Npy, Pomc, and SF-1. That the neurohypophysis is a derivative from this region has been described before (Pearson et al., 2011; Pearson and Placzek, 2013).

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