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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

A possible network of Lhx5-regulated genes and interactions related to MBO development and differentiation. Genes downregulated (red arrows) or upregulated (blue arrows) according to microarray data validated by qPCR have been placed into 5 “bins”. Bins 1–3 contain genes and interactions known to be essential for MBO development (bin 1) or for the development of the hypothalamus (bins 2 and 3). Bin 4 shows transcription factors specifically expressed in the MBO which have not been proven essential for its development. Bin 5 contains effector genes (adhesion, axonal guidance) expressed in the MBO and presumably involved in its differentiation. Lmo1 has a reciprocal regulatory relation with Lhx5 not shared with any of the other candidates. In gray, data from the literature.
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Figure 12: A possible network of Lhx5-regulated genes and interactions related to MBO development and differentiation. Genes downregulated (red arrows) or upregulated (blue arrows) according to microarray data validated by qPCR have been placed into 5 “bins”. Bins 1–3 contain genes and interactions known to be essential for MBO development (bin 1) or for the development of the hypothalamus (bins 2 and 3). Bin 4 shows transcription factors specifically expressed in the MBO which have not been proven essential for its development. Bin 5 contains effector genes (adhesion, axonal guidance) expressed in the MBO and presumably involved in its differentiation. Lmo1 has a reciprocal regulatory relation with Lhx5 not shared with any of the other candidates. In gray, data from the literature.

Mentions: We attempted to elucidate the mechanisms downstream Shh signaling by which the regions of the caudal hypothalamus acquire their identity. The expression domain of Lhx5 is appropriate for this gene to play a role in determining important properties of the caudal hypothalamus. Therefore, we generated a novel mutant allele giving rise to a hypomorph. Subsequent expression analysis with microarrays and other experiments have provided us with a series of candidate genes involved in appropriate differentiation of the MBO. LHX5 regulates directly or indirectly the onset or the maintenance of expression of these genes and is therefore key to MBO development (Figure 12). Two major pathways known to be involved in the development of the tubero-mamillary region could be affected in the Lhx5 mutant. One of them includes transcription factors Olig2 and Otp acting upstream of Sim1 and 2 and finally Foxb1 for differentiation and survival of the MBO. The second involves the restricted inhibition of Shh by Tbx3 to allow for tubero-mamillary 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)

A possible network of Lhx5-regulated genes and interactions related to MBO development and differentiation. Genes downregulated (red arrows) or upregulated (blue arrows) according to microarray data validated by qPCR have been placed into 5 “bins”. Bins 1–3 contain genes and interactions known to be essential for MBO development (bin 1) or for the development of the hypothalamus (bins 2 and 3). Bin 4 shows transcription factors specifically expressed in the MBO which have not been proven essential for its development. Bin 5 contains effector genes (adhesion, axonal guidance) expressed in the MBO and presumably involved in its differentiation. Lmo1 has a reciprocal regulatory relation with Lhx5 not shared with any of the other candidates. In gray, data from the literature.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 12: A possible network of Lhx5-regulated genes and interactions related to MBO development and differentiation. Genes downregulated (red arrows) or upregulated (blue arrows) according to microarray data validated by qPCR have been placed into 5 “bins”. Bins 1–3 contain genes and interactions known to be essential for MBO development (bin 1) or for the development of the hypothalamus (bins 2 and 3). Bin 4 shows transcription factors specifically expressed in the MBO which have not been proven essential for its development. Bin 5 contains effector genes (adhesion, axonal guidance) expressed in the MBO and presumably involved in its differentiation. Lmo1 has a reciprocal regulatory relation with Lhx5 not shared with any of the other candidates. In gray, data from the literature.
Mentions: We attempted to elucidate the mechanisms downstream Shh signaling by which the regions of the caudal hypothalamus acquire their identity. The expression domain of Lhx5 is appropriate for this gene to play a role in determining important properties of the caudal hypothalamus. Therefore, we generated a novel mutant allele giving rise to a hypomorph. Subsequent expression analysis with microarrays and other experiments have provided us with a series of candidate genes involved in appropriate differentiation of the MBO. LHX5 regulates directly or indirectly the onset or the maintenance of expression of these genes and is therefore key to MBO development (Figure 12). Two major pathways known to be involved in the development of the tubero-mamillary region could be affected in the Lhx5 mutant. One of them includes transcription factors Olig2 and Otp acting upstream of Sim1 and 2 and finally Foxb1 for differentiation and survival of the MBO. The second involves the restricted inhibition of Shh by Tbx3 to allow for tubero-mamillary 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.


Related in: MedlinePlus