Evolutionary recruitment of flexible Esrp-dependent splicing programs into diverse embryonic morphogenetic processes

Abstract

Epithelial-mesenchymal interactions are crucial for the development of numerous animal structures. Thus, unraveling how molecular tools are recruited in different lineages to control interplays between these tissues is key to understanding morphogenetic evolution. Here, we study Esrp genes, which regulate extensive splicing programs and are essential for mammalian organogenesis. We find that Esrp homologs have been independently recruited for the development of multiple structures across deuterostomes. Although Esrp is involved in a wide variety of ontogenetic processes, our results suggest ancient roles in non-neural ectoderm and regulating specific mesenchymal-to-epithelial transitions in deuterostome ancestors. However, consistent with the extensive rewiring of Esrp-dependent splicing programs between phyla, most developmental defects observed in vertebrate mutants are related to other types of morphogenetic processes. This is likely connected to the origin of an event in Fgfr, which was recruited as an Esrp target in stem chordates and subsequently co-opted into the development of many novel traits in vertebrates.

Requirement ofIrf6andEsrp1/2in frontonasal and palatal epithelium to regulate craniofacial and palate morphogenesis in mouse and zebrafish

“…No phenotype was observed in the esrp1 -4bp/-4bp embryos, and esrp2 -14bp/-14bp fish developed normally except that females were infertile, as previously published. (Burguera et al, 2017) However, compound homozygote esrp1 -4bp/-4bp ;esrp2 -14bp/-14bp zebrafish exhibit several phenotypes, consistent with previously published mutants. (Burguera et al, 2017) The espr1 -4bp/-4bp ;esrp2 -14bp/-14bp embryos also failed to inflate the swim bladder, and the pectoral fins were formed but diminutive and the margins of the fin appeared dysplastic with irregular morphology.…”

“…(Burguera et al, 2017) However, compound homozygote esrp1 -4bp/-4bp ;esrp2 -14bp/-14bp zebrafish exhibit several phenotypes, consistent with previously published mutants. (Burguera et al, 2017) The espr1 -4bp/-4bp ;esrp2 -14bp/-14bp embryos also failed to inflate the swim bladder, and the pectoral fins were formed but diminutive and the margins of the fin appeared dysplastic with irregular morphology. Further, Alcian blue staining of double knockouts revealed cleft in the anterior neurocranium, but the ventral cartilages, including the Meckel's cartilage, were formed and appeared wild type ( Fig.…”

“…Gene expression domains of irf6, esrp1, and esrp2 overlap significantly, consistent with previous reports. (Burguera et al, 2017) To resolve the specific cell population of the embryonic epithelium that express irf6, esrp1, and esrp2, we performed RNAscope in-situ hybridization of coronal cryosections taken through the developing mouth and palate at 48 and 72 hours post-fertilization (hpf). We find that irf6 and esrp1 are co-expressed within epithelial cells lining the oral cavity as well as the surface epithelium ( Fig.…”

“…(Bebee et al, 2015) Esrp1/2 are unusual among regulators of RNA-splicing in that they are tissue-restricted and exhibit dynamic expression during embryogenesis. (Bebee et al, 2015;Burguera et al, 2017) The developmental importance of Esrp1/2 is underscored by their conservation across species, from ascidians to zebrafish, Xenopus, mouse, and humans. (Burguera et al, 2017) Gene variant in ESRP2 was also recently reported in human orofacial cleft cohorts.…”

“…(Bebee et al, 2015;Burguera et al, 2017) The developmental importance of Esrp1/2 is underscored by their conservation across species, from ascidians to zebrafish, Xenopus, mouse, and humans. (Burguera et al, 2017) Gene variant in ESRP2 was also recently reported in human orofacial cleft cohorts. (Cox et al, 2018) The mouse has been an important model utilized to study the role of specific human orofacial cleft gene variants on palate development as well as to elucidate gene regulatory pathways that control proper craniofacial morphogenesis.…”