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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.


Expression of Lhx5 in the mamillary region. In situ hybridization for Lhx5 on sagittal sections (rostral to the left) of E11.5 (A,B) and E18.5 (C,D) brains. Lhx5 is expressed in the ventricular zone (neuroepithelium; arrow in (A) and inset in (A) as well as in the incipient mamillary mantle layer (arrow in B). At E18.5, the MBO is prominently and specifically labeled in the mamillary region (framed in C, magnified in D). Abbreviations: 4V, fourth ventricle; ac, anterior commissure; cf, cephalic flexure; MB, midbrain; MBO, mamillary body; MO, medulla oblongata; P, pons; Th, thalamus. In (C,D) a dashed line brings out the contour of the brain. Scale bars: 500 μm.
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Figure 1: Expression of Lhx5 in the mamillary region. In situ hybridization for Lhx5 on sagittal sections (rostral to the left) of E11.5 (A,B) and E18.5 (C,D) brains. Lhx5 is expressed in the ventricular zone (neuroepithelium; arrow in (A) and inset in (A) as well as in the incipient mamillary mantle layer (arrow in B). At E18.5, the MBO is prominently and specifically labeled in the mamillary region (framed in C, magnified in D). Abbreviations: 4V, fourth ventricle; ac, anterior commissure; cf, cephalic flexure; MB, midbrain; MBO, mamillary body; MO, medulla oblongata; P, pons; Th, thalamus. In (C,D) a dashed line brings out the contour of the brain. Scale bars: 500 μm.

Mentions: LHX5 is a member of the LHX family of transcription factors acting as important differentiation determinants (Hobert and Westphal, 2000; Kadrmas and Beckerle, 2004), and it is strongly expressed in the caudal hypothalamus from very early stages (E9.5) through the time of formation of recognizable neuronal aggregates (Figures 1A–D) (Sheng et al., 1997; Allen-Institute-for-Brain-Science, 2009; Shimogori et al., 2010). Lhx5 has specific roles in forebrain development— e.g., it is essential for hippocampal development (Zhao et al., 1999) and regulates the distribution of Cajal-Retzius neurons (Miquelajáuregui et al., 2010). Here we created a novel mutant allele of Lhx5 and analyzed it using expression profiling with microarrays, ChIP-Seq and luciferase experiments, as well as examination of the hypothalamus of the Tbx3−∕−. Our results indicate that Lhx5 has an essential role in several different developmental pathways regulating MBO specification and differentiation.


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)

Expression of Lhx5 in the mamillary region. In situ hybridization for Lhx5 on sagittal sections (rostral to the left) of E11.5 (A,B) and E18.5 (C,D) brains. Lhx5 is expressed in the ventricular zone (neuroepithelium; arrow in (A) and inset in (A) as well as in the incipient mamillary mantle layer (arrow in B). At E18.5, the MBO is prominently and specifically labeled in the mamillary region (framed in C, magnified in D). Abbreviations: 4V, fourth ventricle; ac, anterior commissure; cf, cephalic flexure; MB, midbrain; MBO, mamillary body; MO, medulla oblongata; P, pons; Th, thalamus. In (C,D) a dashed line brings out the contour of the brain. Scale bars: 500 μm.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: Expression of Lhx5 in the mamillary region. In situ hybridization for Lhx5 on sagittal sections (rostral to the left) of E11.5 (A,B) and E18.5 (C,D) brains. Lhx5 is expressed in the ventricular zone (neuroepithelium; arrow in (A) and inset in (A) as well as in the incipient mamillary mantle layer (arrow in B). At E18.5, the MBO is prominently and specifically labeled in the mamillary region (framed in C, magnified in D). Abbreviations: 4V, fourth ventricle; ac, anterior commissure; cf, cephalic flexure; MB, midbrain; MBO, mamillary body; MO, medulla oblongata; P, pons; Th, thalamus. In (C,D) a dashed line brings out the contour of the brain. Scale bars: 500 μm.
Mentions: LHX5 is a member of the LHX family of transcription factors acting as important differentiation determinants (Hobert and Westphal, 2000; Kadrmas and Beckerle, 2004), and it is strongly expressed in the caudal hypothalamus from very early stages (E9.5) through the time of formation of recognizable neuronal aggregates (Figures 1A–D) (Sheng et al., 1997; Allen-Institute-for-Brain-Science, 2009; Shimogori et al., 2010). Lhx5 has specific roles in forebrain development— e.g., it is essential for hippocampal development (Zhao et al., 1999) and regulates the distribution of Cajal-Retzius neurons (Miquelajáuregui et al., 2010). Here we created a novel mutant allele of Lhx5 and analyzed it using expression profiling with microarrays, ChIP-Seq and luciferase experiments, as well as examination of the hypothalamus of the Tbx3−∕−. Our results indicate that Lhx5 has an essential role in several different developmental pathways regulating MBO specification and differentiation.

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.