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Wnt Signaling Pathways Are Dysregulated in Rat Female Cerebellum Following Early Methyl Donor Deficiency

Abstract

Gestational methyl donor (especially B9 and B12 vitamins) deficiency is involved in birth defects and brain development retardation. The underlying molecular mechanisms that are dysregulated still remain poorly understood, in particular in the cerebellum. As evidenced from previous data, females are more affected than males. In this study, we therefore took advantage of a validated rat nutritional model and performed a microarray analysis on female progeny cerebellum, in order to identify which genes and molecular pathways were disrupted in response to methyl donor deficiency. We found that cerebellum development is altered in female pups, with a decrease of the granular cell layer thickness at postnatal day 21. Furthermore, we investigated the involvement of the Wnt signaling pathway, a major molecular pathway involved in neuronal development and later on in synaptic assembly and neurotransmission processes. We found that Wnt canonical pathway was disrupted following early methyl donor deficiency and that neuronal targets were selectively enriched in the downregulated genes. These results could explain the structural brain defects previously observed and highlighted new genes and a new molecular pathway affected by nutritional methyl donor deprivation.

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Funding

Institutional grants were received from the Region of Lorraine (France).

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Correspondence to Brigitte Leininger-Muller or Natacha Dreumont.

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The authors declare that they have no conflict of interest.

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The data discussed in this publication have been deposited in NCBI’s Gene Expression Omnibus and are accessible through GEO Series accession number GSE104164 (https://www-ncbi-nlm-nih-gov.gate2.inist.fr/geo/query/acc.cgi?acc=GSE104164).

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Willekens, J., Hergalant, S., Pourié, G. et al. Wnt Signaling Pathways Are Dysregulated in Rat Female Cerebellum Following Early Methyl Donor Deficiency. Mol Neurobiol 56, 892–906 (2019). https://doi.org/10.1007/s12035-018-1128-3

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  • DOI: https://doi.org/10.1007/s12035-018-1128-3

Keywords

  • Methyl donor deficiency
  • Cerebellum
  • Transcriptomics
  • Wnt signaling pathway
  • Neuroplasticity