title: Loss of Sip1 leads to migration defects and retention of ectodermal markers during lens development.
abstract: SIP1 encodes a DNA-binding transcription factor that regulates multiple developmental processes, as highlighted by the pleiotropic defects observed in Mowat-Wilson syndrome, which results from mutations in this gene. Further, in adults, dysregulated SIP1 expression has been implicated in both cancer and fibrotic diseases, where it functionally links TGFβ signaling to the loss of epithelial cell characteristics and gene expression. In the ocular lens, an epithelial tissue important for vision, Sip1 is co-expressed with epithelial markers, such as E-cadherin, and is required for the complete separation of the lens vesicle from the head ectoderm during early ocular morphogenesis. However, the function of Sip1 after early lens morphogenesis is still unknown. Here, we conditionally deleted Sip1 from the developing mouse lens shortly after lens vesicle closure, leading to defects in coordinated fiber cell tip migration, defective suture formation, and cataract. Interestingly, RNA-Sequencing analysis on Sip1 knockout lenses identified 190 differentially expressed genes, all of which are distinct from previously described Sip1 target genes. Furthermore, 34% of the genes with increased expression in the Sip1 knockout lenses are normally downregulated as the lens transitions from the lens vesicle to early lens, while 49% of the genes with decreased expression in the Sip1 knockout lenses are normally upregulated during early lens development. Overall, these data imply that Sip1 plays a major role in reprogramming the lens vesicle away from a surface ectoderm cell fate towards that necessary for the development of a transparent lens and demonstrate that Sip1 regulates distinctly different sets of genes in different cellular contexts.
authors.affiliation: Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA.
authors.forename: Abby L
authors.initials: AL
authors.lastname: Manthey
authors.affiliation: Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA; Center for Bioinformatics and Computational Biology, University of Delaware, Newark, DE 19716, USA.
authors.forename: Salil A
authors.initials: SA
authors.lastname: Lachke
authors.affiliation: Department of Cell Biology and Human Anatomy, School of Medicine, University of California, Davis, CA 95616, USA.
authors.forename: Paul G
authors.initials: PG
authors.lastname: FitzGerald
authors.affiliation: Department of Biomedical Research, Alfred I duPont Hospital for Children, Wilmington, DE 19803, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Mason
authors.affiliation: Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Scheiblin
authors.affiliation: Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: McDonald
authors.affiliation: Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA. Electronic address: duncanm@udel.edu.
authors.forename: Melinda K
authors.initials: MK
authors.lastname: Duncan
mesh_terms: D000818:Animals; D015415:Biomarkers; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D004475:Ectoderm / Q000254:growth & development / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D019066:Facies; D018507:Gene Expression Regulation, Developmental; D006627:Hirschsprung Disease / Q000235:genetics*; D008607:Intellectual Disability / Q000235:genetics*; D007908:Lens, Crystalline / Q000254:growth & development* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008831:Microcephaly / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D017423:Sequence Analysis, RNA
chemical_list: D015415:Biomarkers; D015820:Cadherins; D009419:Nerve Tissue Proteins; C491561:Sip1 protein, mouse
keywords: Ectodermal cell fate; Lens development; Sip1; Zeb2