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Lhx5 controls mamillary differentiation in the developing hypothalamus of the mouse.

Heide M, Zhang Y, Zhou X, Zhao T, Miquelajáuregui A, Varela-Echavarría A, Alvarez-Bolado G - Front Neuroanat (2015)

Bottom Line: Microarray analysis and chromatin immunoprecipitation indicated that Lhx5 appears to be involved in Shh downregulation through Tbx3 and activates several MBO-specific regulator and effector genes.Finally, by tracing the caudal hypothalamic cell lineage we show that, in the Lhx5 mutant, at least some MBO cells are present but lack characteristic marker expression.Our work shows how the Lhx5 locus contributes to integrate regional specification pathways with downstream acquisition of neuronal identity in the MBO.

View Article: PubMed Central - PubMed

Affiliation: Institute of Anatomy and Cell Biology, University of Heidelberg Heidelberg, Germany.

ABSTRACT
Acquisition of specific neuronal identity by individual brain nuclei is a key step in brain development. However, how the mechanisms that confer neuronal identity are integrated with upstream regional specification networks is still mysterious. Expression of Sonic hedgehog (Shh), is required for hypothalamic specification and is later downregulated by Tbx3 to allow for the differentiation of the tubero-mamillary region. In this region, the mamillary body (MBO), is a large neuronal aggregate essential for memory formation. To clarify how MBO identity is acquired after regional specification, we investigated Lhx5, a transcription factor with restricted MBO expression. We first generated a hypomorph allele of Lhx5-in homozygotes, the MBO disappears after initial specification. Intriguingly, in these mutants, Tbx3 was downregulated and the Shh expression domain abnormally extended. Microarray analysis and chromatin immunoprecipitation indicated that Lhx5 appears to be involved in Shh downregulation through Tbx3 and activates several MBO-specific regulator and effector genes. Finally, by tracing the caudal hypothalamic cell lineage we show that, in the Lhx5 mutant, at least some MBO cells are present but lack characteristic marker expression. Our work shows how the Lhx5 locus contributes to integrate regional specification pathways with downstream acquisition of neuronal identity in the MBO.

No MeSH data available.


Shh domain expanded in the Lhx5fl∕fl mutant. In situ detection of Shh expression in Lhx5fl∕+ and Lhx5fl∕fl mutant E11.5 (A,B) and E12.5 (C,D) embryos. Lines with arrowed ends indicate the size of the Shh-free region in the midline. Scale bars: 500 μm.
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Figure 9: Shh domain expanded in the Lhx5fl∕fl mutant. In situ detection of Shh expression in Lhx5fl∕+ and Lhx5fl∕fl mutant E11.5 (A,B) and E12.5 (C,D) embryos. Lines with arrowed ends indicate the size of the Shh-free region in the midline. Scale bars: 500 μm.

Mentions: The reduction in Tbx3 is very intriguing, since this gene (Tbx2 in chicken) is needed to inhibit Shh expression in the tubero-mamillary region (Manning et al., 2006; Trowe et al., 2013), an event indispensable for this region to differentiate (Manning et al., 2006). We hypothesized that the downregulation of Tbx3 in Lhx5 mutants would result in an abnormal expansion of the territory of Shh in the caudal hypothalamus. In situ detection of Shh expression confirmed that, in the Lhx5 mutants, the domain where Shh is normally downregulated becomes very small (Figures 9A,B). We obtained similar results at E12.5, when Shh expression is at its peak in this region, after which it starts to disappear (Figures 9C,D). We concluded that failure to completely inhibit Shh expression in the tubero-mamillary region is a possible mechanism explaining the MBO phenotype that we observe in the Lhx5 mutants.


Lhx5 controls mamillary differentiation in the developing hypothalamus of the mouse.

Heide M, Zhang Y, Zhou X, Zhao T, Miquelajáuregui A, Varela-Echavarría A, Alvarez-Bolado G - Front Neuroanat (2015)

Shh domain expanded in the Lhx5fl∕fl mutant. In situ detection of Shh expression in Lhx5fl∕+ and Lhx5fl∕fl mutant E11.5 (A,B) and E12.5 (C,D) embryos. Lines with arrowed ends indicate the size of the Shh-free region in the midline. Scale bars: 500 μm.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4536661&req=5

Figure 9: Shh domain expanded in the Lhx5fl∕fl mutant. In situ detection of Shh expression in Lhx5fl∕+ and Lhx5fl∕fl mutant E11.5 (A,B) and E12.5 (C,D) embryos. Lines with arrowed ends indicate the size of the Shh-free region in the midline. Scale bars: 500 μm.
Mentions: The reduction in Tbx3 is very intriguing, since this gene (Tbx2 in chicken) is needed to inhibit Shh expression in the tubero-mamillary region (Manning et al., 2006; Trowe et al., 2013), an event indispensable for this region to differentiate (Manning et al., 2006). We hypothesized that the downregulation of Tbx3 in Lhx5 mutants would result in an abnormal expansion of the territory of Shh in the caudal hypothalamus. In situ detection of Shh expression confirmed that, in the Lhx5 mutants, the domain where Shh is normally downregulated becomes very small (Figures 9A,B). We obtained similar results at E12.5, when Shh expression is at its peak in this region, after which it starts to disappear (Figures 9C,D). We concluded that failure to completely inhibit Shh expression in the tubero-mamillary region is a possible mechanism explaining the MBO phenotype that we observe in the Lhx5 mutants.

Bottom Line: Microarray analysis and chromatin immunoprecipitation indicated that Lhx5 appears to be involved in Shh downregulation through Tbx3 and activates several MBO-specific regulator and effector genes.Finally, by tracing the caudal hypothalamic cell lineage we show that, in the Lhx5 mutant, at least some MBO cells are present but lack characteristic marker expression.Our work shows how the Lhx5 locus contributes to integrate regional specification pathways with downstream acquisition of neuronal identity in the MBO.

View Article: PubMed Central - PubMed

Affiliation: Institute of Anatomy and Cell Biology, University of Heidelberg Heidelberg, Germany.

ABSTRACT
Acquisition of specific neuronal identity by individual brain nuclei is a key step in brain development. However, how the mechanisms that confer neuronal identity are integrated with upstream regional specification networks is still mysterious. Expression of Sonic hedgehog (Shh), is required for hypothalamic specification and is later downregulated by Tbx3 to allow for the differentiation of the tubero-mamillary region. In this region, the mamillary body (MBO), is a large neuronal aggregate essential for memory formation. To clarify how MBO identity is acquired after regional specification, we investigated Lhx5, a transcription factor with restricted MBO expression. We first generated a hypomorph allele of Lhx5-in homozygotes, the MBO disappears after initial specification. Intriguingly, in these mutants, Tbx3 was downregulated and the Shh expression domain abnormally extended. Microarray analysis and chromatin immunoprecipitation indicated that Lhx5 appears to be involved in Shh downregulation through Tbx3 and activates several MBO-specific regulator and effector genes. Finally, by tracing the caudal hypothalamic cell lineage we show that, in the Lhx5 mutant, at least some MBO cells are present but lack characteristic marker expression. Our work shows how the Lhx5 locus contributes to integrate regional specification pathways with downstream acquisition of neuronal identity in the MBO.

No MeSH data available.