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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.


Related in: MedlinePlus

Lhx5 mRNA and LHX5 protein in Lhx5fl∕fl mutants. (A,B) Nissl staining of the hippocampus of Lhx5fl∕+(A) and Lhx5fl∕fl mutant (B) E18.5 embryos. Arrows indicate the dentate gyrus in (A) and its absence in (B). (C,D) Immunohistochemistry against calretinin (red) on Lhx5fl∕+ and Lhx5fl∕fl mutant E12.5 embryos, counterstaining with DAPI (blue). Arrows in (C,D) show the presence of an ectopic Cajal-Retzius cell cluster in the mutant telencephalon. Scale bars: (A,B): 500 μm; (C,D): 100 μm.
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Figure 3: Lhx5 mRNA and LHX5 protein in Lhx5fl∕fl mutants. (A,B) Nissl staining of the hippocampus of Lhx5fl∕+(A) and Lhx5fl∕fl mutant (B) E18.5 embryos. Arrows indicate the dentate gyrus in (A) and its absence in (B). (C,D) Immunohistochemistry against calretinin (red) on Lhx5fl∕+ and Lhx5fl∕fl mutant E12.5 embryos, counterstaining with DAPI (blue). Arrows in (C,D) show the presence of an ectopic Cajal-Retzius cell cluster in the mutant telencephalon. Scale bars: (A,B): 500 μm; (C,D): 100 μm.

Mentions: Moreover, phenotypical analysis of Lhx5fl∕fl embryos prior to Cre-recombination revealed a mutant phenotype resembling the published phenotypes of the Lhx5 full mutant— a defective hippocampus (Figures 3A,B) (Zhao et al., 1999) and ectopic Cajal Retzius cells forming a cluster in the caudal telencephalon (Figures 3C,D) (Miquelajáuregui et al., 2010).


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)

Lhx5 mRNA and LHX5 protein in Lhx5fl∕fl mutants. (A,B) Nissl staining of the hippocampus of Lhx5fl∕+(A) and Lhx5fl∕fl mutant (B) E18.5 embryos. Arrows indicate the dentate gyrus in (A) and its absence in (B). (C,D) Immunohistochemistry against calretinin (red) on Lhx5fl∕+ and Lhx5fl∕fl mutant E12.5 embryos, counterstaining with DAPI (blue). Arrows in (C,D) show the presence of an ectopic Cajal-Retzius cell cluster in the mutant telencephalon. Scale bars: (A,B): 500 μm; (C,D): 100 μm.
© Copyright Policy
Related In: Results  -  Collection

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Figure 3: Lhx5 mRNA and LHX5 protein in Lhx5fl∕fl mutants. (A,B) Nissl staining of the hippocampus of Lhx5fl∕+(A) and Lhx5fl∕fl mutant (B) E18.5 embryos. Arrows indicate the dentate gyrus in (A) and its absence in (B). (C,D) Immunohistochemistry against calretinin (red) on Lhx5fl∕+ and Lhx5fl∕fl mutant E12.5 embryos, counterstaining with DAPI (blue). Arrows in (C,D) show the presence of an ectopic Cajal-Retzius cell cluster in the mutant telencephalon. Scale bars: (A,B): 500 μm; (C,D): 100 μm.
Mentions: Moreover, phenotypical analysis of Lhx5fl∕fl embryos prior to Cre-recombination revealed a mutant phenotype resembling the published phenotypes of the Lhx5 full mutant— a defective hippocampus (Figures 3A,B) (Zhao et al., 1999) and ectopic Cajal Retzius cells forming a cluster in the caudal telencephalon (Figures 3C,D) (Miquelajáuregui et al., 2010).

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.


Related in: MedlinePlus