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Genome-wide characterisation of Foxa1 binding sites reveals several mechanisms for regulating neuronal differentiation in midbrain dopamine cells.

Metzakopian E, Bouhali K, Alvarez-Saavedra M, Whitsett JA, Picketts DJ, Ang SL - Development (2015)

Bottom Line: Interestingly, our studies identified a rostral brain floor plate Neurog2 enhancer that requires direct input from Otx2, Foxa1, Foxa2 and an E-box transcription factor for its transcriptional activity.Furthermore, the chromatin remodelling factor Smarca1 was shown to function downstream of Foxa1 and Foxa2 to regulate differentiation from immature to mature midbrain dopaminergic neurons.Our genome-wide Foxa1-bound cis-regulatory sequences from ChIP-Seq and Foxa1/2 candidate target genes from RNA-Seq analyses of embryonic midbrain dopamine cells also provide an excellent resource for probing mechanistic insights into gene regulatory networks involved in the differentiation of midbrain dopamine neurons.

View Article: PubMed Central - PubMed

Affiliation: Department of Developmental Neurobiology, NIMR, The Ridgeway, London NW7 1AA, UK.

No MeSH data available.


Related in: MedlinePlus

Smarca1 is required for maturation of a subset of mDA neurons. (A,B) Whereas the total number of Nurr1+ mDA neurons remains unchanged, the numbers of mature Th+ and Pitx3+ mDA neurons are reduced by ∼25% in the Smarca1 mutant at E12.5. The average±s.e.m. of at least three independent replicates is shown. *P<0.05 (two-tailed t-test).
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DEV115808F5: Smarca1 is required for maturation of a subset of mDA neurons. (A,B) Whereas the total number of Nurr1+ mDA neurons remains unchanged, the numbers of mature Th+ and Pitx3+ mDA neurons are reduced by ∼25% in the Smarca1 mutant at E12.5. The average±s.e.m. of at least three independent replicates is shown. *P<0.05 (two-tailed t-test).

Mentions: Given recent studies suggesting a role of epigenetic factors in the regulation of mDA neuronal differentiation (reviewed by van Heesbeen et al., 2013; Yi et al., 2014), we focused on the role of Smarca1 in the differentiation of mDA neurons. Smarca1 has previously been shown to promote the differentiation of neuronal progenitors in the cortex (Yip et al., 2012), but its role in the midbrain was not examined. We generated Smarca1−/− embryos to determine whether it has a role in the development of mDA neurons (Fig. 5).Fig. 5.


Genome-wide characterisation of Foxa1 binding sites reveals several mechanisms for regulating neuronal differentiation in midbrain dopamine cells.

Metzakopian E, Bouhali K, Alvarez-Saavedra M, Whitsett JA, Picketts DJ, Ang SL - Development (2015)

Smarca1 is required for maturation of a subset of mDA neurons. (A,B) Whereas the total number of Nurr1+ mDA neurons remains unchanged, the numbers of mature Th+ and Pitx3+ mDA neurons are reduced by ∼25% in the Smarca1 mutant at E12.5. The average±s.e.m. of at least three independent replicates is shown. *P<0.05 (two-tailed t-test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4378246&req=5

DEV115808F5: Smarca1 is required for maturation of a subset of mDA neurons. (A,B) Whereas the total number of Nurr1+ mDA neurons remains unchanged, the numbers of mature Th+ and Pitx3+ mDA neurons are reduced by ∼25% in the Smarca1 mutant at E12.5. The average±s.e.m. of at least three independent replicates is shown. *P<0.05 (two-tailed t-test).
Mentions: Given recent studies suggesting a role of epigenetic factors in the regulation of mDA neuronal differentiation (reviewed by van Heesbeen et al., 2013; Yi et al., 2014), we focused on the role of Smarca1 in the differentiation of mDA neurons. Smarca1 has previously been shown to promote the differentiation of neuronal progenitors in the cortex (Yip et al., 2012), but its role in the midbrain was not examined. We generated Smarca1−/− embryos to determine whether it has a role in the development of mDA neurons (Fig. 5).Fig. 5.

Bottom Line: Interestingly, our studies identified a rostral brain floor plate Neurog2 enhancer that requires direct input from Otx2, Foxa1, Foxa2 and an E-box transcription factor for its transcriptional activity.Furthermore, the chromatin remodelling factor Smarca1 was shown to function downstream of Foxa1 and Foxa2 to regulate differentiation from immature to mature midbrain dopaminergic neurons.Our genome-wide Foxa1-bound cis-regulatory sequences from ChIP-Seq and Foxa1/2 candidate target genes from RNA-Seq analyses of embryonic midbrain dopamine cells also provide an excellent resource for probing mechanistic insights into gene regulatory networks involved in the differentiation of midbrain dopamine neurons.

View Article: PubMed Central - PubMed

Affiliation: Department of Developmental Neurobiology, NIMR, The Ridgeway, London NW7 1AA, UK.

No MeSH data available.


Related in: MedlinePlus