Anteroposterior patterning of the zebrafish ear through Fgf- and Hh-dependent regulation of hmx3a expression

• Published in: PLoS genetics 2019-04, Vol.15 (4), p.e1008051-e1008051
• Main Authors: Hartwell, Ryan D, England, Samantha J, Monk, Nicholas A M, van Hateren, Nicholas J, Baxendale, Sarah, Marzo, Mar, Lewis, Katharine E, Whitfield, Tanya T
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Asymmetry; Biology and Life Sciences; Body Patterning - genetics; CRISPR; Danio rerio; Developmental biology; Ear; Ear - embryology; Ears & hearing; Ectopic expression; Embryo, Nonmammalian; Fibroblast growth factor 3; Fibroblast growth factors; Fibroblast Growth Factors - metabolism; Fibroblasts; Funding; Gene expression; Gene Expression Regulation, Developmental; Genetic aspects; Genetic engineering; Genomes; Growth factors; Hedgehog Proteins - metabolism; Mathematical models; Medicine and Health Sciences; Phenotype; Physiological aspects; Research and Analysis Methods; Signal Transduction; Symmetry (Biology); Transcription; Transcription factors; Transcription Factors - genetics; Zebrafish; Zebrafish - embryology; Zebrafish - physiology; Zebrafish Proteins - genetics
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1008051

In the zebrafish, Fgf and Hh signalling assign anterior and posterior identity, respectively, to the poles of the developing ear. Mis-expression of fgf3 or inhibition of Hh signalling results in double-anterior ears, including ectopic expression of hmx3a. To understand how this double-anterior pattern is established, we characterised transcriptional responses in Fgf gain-of-signalling or Hh loss-of-signalling backgrounds. Mis-expression of fgf3 resulted in rapid expansion of anterior otic markers, refining over time to give the duplicated pattern. Response to Hh inhibition was very different: initial anteroposterior asymmetry was retained, with de novo duplicate expression domains appearing later. We show that Hmx3a is required for normal anterior otic patterning, and that otic patterning defects in hmx3a-/- mutants are a close phenocopy to those seen in fgf3-/- mutants. However, neither loss nor gain of hmx3a function was sufficient to generate full ear duplications. Using our data to infer a transcriptional regulatory network required for acquisition of otic anterior identity, we can recapitulate both the wild-type and the double-anterior pattern in a mathematical model.