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Preprints

Zebrafish her3 knockout impacts developmental and cancer-related gene signatures

Kent MR, Calderon D, Silvius KM, LaVigne CA, Cannon MV, Kendall GC.
Preprint from
bioRxiv
26 February 2022
PPR
PPR462132
Abstract
HES3 is a basic helix-loop-helix transcription factor that regulates neural stem cell renewal during development. HES3 overexpression is predictive of reduced overall survival in patients with fusion-positive rhabdomyosarcoma, a pediatric cancer that resembles immature and undifferentiated skeletal muscle. However, the mechanisms of HES3 cooperation in fusion-positive rhabdomyosarcoma are unclear and are likely related to her3 / HES3’s role in neurogenesis. To investigate HES3’s function during development, we generated a zebrafish CRISPR/Cas9 knockout of her3 , the zebrafish ortholog of HES3 . Loss of her3 is not embryonic lethal and adults exhibit expected Mendelian ratios. Embryonic her3 zebrafish mutants are significantly smaller than wildtype and a subset present with lens defects as adults. Transcriptomic analysis of her3 mutant embryos indicates that genes involved in organ development, such as pctp and grinab , are significantly downregulated. Further, differentially expressed genes in her3 knockout embryos are enriched for HOX and SOX10 motifs. Several cancer-related gene pathways are impacted, including the inhibition of matrix metalloproteinases. Altogether, this new model is a powerful system to study her3/HES3 -mediated neural development and its misappropriation in cancer contexts.

Summary Statement

Here, we generate and characterize a zebrafish her3 / HES3 knockout to elucidate the functional role of her3 / HES3 , a transcriptional repressor, in neural development and tumorigenic processes.