Abstract
BackgroundDespite the fundamental biological importance and clinical relevance of characterizing the effects of chronic hypoxia exposure on central nervous system (CNS) development, the changes in gene expression from hypoxia are unknown. It is not known if there are unifying principles, properties, or logic in the response of the developing CNS to hypoxic exposure. Here, we use the small vertebrate zebrafish (Danio rerio) to study the effects of hypoxia on connectivity gene expression across development. We perform transcriptional profiling at high temporal resolution to systematically determine and then experimentally validate the response of CNS connectivity genes to hypoxia exposure.ResultsWe characterized mRNA changes during development, comparing the effects of chronic hypoxia exposure at different time-points. We focused on changes in expression levels of a subset of 1270 genes selected for their roles in development of CNS connectivity, including axon pathfinding and synapse formation. We found that the majority of CNS connectivity genes were unaffected by hypoxia. However, for a small subset of genes hypoxia significantly affected their gene expression profiles. In particular, hypoxia appeared to affect both the timing and levels of expression, including altering expression of interacting gene pairs in a fashion that would potentially disrupt normal function.ConclusionsOverall, our study identifies the response of CNS connectivity genes to hypoxia exposure during development. While for most genes hypoxia did not significantly affect expression, for a subset of genes hypoxia changed both levels and timing of expression. Importantly, we identified that some genes with interacting proteins, for example receptor/ligand pairs, had dissimilar responses to hypoxia that would be expected to interfere with their function. The observed dysynchrony of gene expression could impair the development of normal CNS connectivity maps.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2638-x) contains supplementary material, which is available to authorized users.
Highlights
Despite the fundamental biological importance and clinical relevance of characterizing the effects of chronic hypoxia exposure on central nervous system (CNS) development, the changes in gene expression from hypoxia are unknown
Experimental studies have demonstrated that developmental hypoxia can disrupt axon pathfinding [12, 13] and alter synapse gene expression [14]. hif1α, a basic helixloop-helix transcription factor whose protein expression is stabilized in hypoxia, controls many of the downstream responses to hypoxia including in the CNS [15]
We found that the majority of CNS connectivity genes were unaffected by hypoxia
Summary
Despite the fundamental biological importance and clinical relevance of characterizing the effects of chronic hypoxia exposure on central nervous system (CNS) development, the changes in gene expression from hypoxia are unknown. It is not known if there are unifying principles, properties, or logic in the response of the developing CNS to hypoxic exposure. We use the small vertebrate zebrafish (Danio rerio) to study the effects of hypoxia on connectivity gene expression across development. Despite the significant clinical impact, the specific effects of hypoxia on the developing central nervous system (CNS) are poorly characterized, and the molecular mechanisms largely unknown. A small number of target genes involved in CNS connectivity and dysregulated by hypoxia have been identified and experimentally validated; including adenosine A2 receptor, Brn3b, EphrinB2, Netrin-4, and VAB-1 [12, 13, 17,18,19]
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