Time Course Transcriptome Analysis of Spina Bifida Progression in Fetal Rats.

Kendall P Murphy,Jose L Peiro,Bedika Pathak,Marc Oria

doi:10.3390/brainsci11121593

Abstract

A better understanding of the transcriptomic modifications that occur in spina bifida may lead to identify mechanisms involved in the progression of spina bifida in utero and the development of new therapeutic strategies that aid in spinal cord regeneration after surgical interventions. In this study, RNA-sequencing was used to identify differentially expressed genes in fetal spinal cords from rats with retinoic acid-induced spina bifida at E15, E17, and E20. Gene ontology, KEGG, and protein–protein interaction analysis were conducted to predict pathways involved in the evolution of the disease. Approximately 3000, 1000 and 300 genes were differentially expressed compared to the control groups at E15, E17 and E20, respectively. Overall, the results suggest common alterations in certain pathways between gestational time points, such as upregulation in p53 and sonic hedgehog signaling at E15 and E17 and downregulation in the myelin sheath at E17 and E20. However, there were other modifications specific to gestational time points, including skeletal muscle development at E15, downregulated glucose metabolism at E17, and upregulated inflammation at E20. In conclusion, this work provides evidence that gestational age during spina bifida repair may be a significant variable to consider during the development of new regenerative therapeutics approaches.

Highlights

Myelomeningocele (MMC), the most significant form of spina bifida, is a devastating congenital malformation of the spinal cord associated with severe morbidity and mortality [1]
This “two-hit” process occurs during the folding of the neural plate into the neural tube during early development, 3–4 weeks of gestation, resulting in the lack of sclerotomal coverage leaving the neural tissue directly exposed to the amniotic fluid [2,3], called the “first hit” followed by an in utero acquired neurodegeneration by the chemical action of the amniotic fluid to the neural tissue or “second hit”
At E15, we identified a cluster of interactions between upregulated differentially expressed genes (DEGs) involved in structure and skeletal muscle development including Acta1, Actn2, and Myog (Figure 9B)

Summary

Introduction

Myelomeningocele (MMC), the most significant form of spina bifida, is a devastating congenital malformation of the spinal cord associated with severe morbidity and mortality [1] This “two-hit” process occurs during the folding of the neural plate into the neural tube during early development, 3–4 weeks of gestation, resulting in the lack of sclerotomal coverage leaving the neural tissue directly exposed to the amniotic fluid [2,3], called the “first hit” followed by an in utero acquired neurodegeneration by the chemical action of the amniotic fluid to the neural tissue or “second hit”. The analysis of transcriptome studies at different time points throughout gestation would provide in-depth knowledge of the regulatory changes present in the neural tissue of the neurodegenerative progression in utero after spina bifida occurs Through these studies, pathways could be identified as therapeutic targets to aid in spinal cord regeneration

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Discussion

Conclusion