title: Temporal Dysynchrony in brain connectivity gene expression following hypoxia.
abstract: 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. 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.
  
  
  
  We 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.
  
  
  
  Overall, 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.
authors.affiliation: Bioinformatics Shared Resource, Huntsman Cancer Institute, Salt Lake City, USA.
authors.forename: Brett
authors.initials: B
authors.lastname: Milash
authors.affiliation: Department of Pediatrics, University of Utah, 295 Chipeta Way, 84108, Salt Lake City, UT, USA.
authors.forename: Jingxia
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Pediatrics, University of Utah, 295 Chipeta Way, 84108, Salt Lake City, UT, USA.
authors.forename: Tamara J
authors.initials: TJ
authors.lastname: Stevenson
authors.affiliation: Department of Pediatrics, University of Utah, 295 Chipeta Way, 84108, Salt Lake City, UT, USA.
authors.forename: Jong-Hyun
authors.initials: JH
authors.lastname: Son
authors.affiliation: Department of Pediatrics, University of Utah, 295 Chipeta Way, 84108, Salt Lake City, UT, USA.
authors.forename: Tiffanie
authors.initials: T
authors.lastname: Dahl
authors.affiliation: Department of Pediatrics, University of Utah, 295 Chipeta Way, 84108, Salt Lake City, UT, USA. joshua.bonkowsky@hsc.utah.edu.|Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, UT, USA. joshua.bonkowsky@hsc.utah.edu.
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Bonkowsky
mesh_terms: D000818:Animals; D063132:Connectome / Q000379:methods*; D020869:Gene Expression Profiling / Q000379:methods*; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D002534:Hypoxia, Brain / Q000235:genetics* / Q000662:veterinary; D017423:Sequence Analysis, RNA; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics
chemical_list: D029961:Zebrafish Proteins
keywords: Axon pathfinding; Connectivity; Hypoxia; Synapse; Zebrafish