Loss of Sip1 leads to migration defects and retention of ectodermal markers during lens development

Abby L. Manthey, Salil A. Lachke, Paul G FitzGerald, Robert W. Mason, David A. Scheiblin, John H. McDonald, Melinda K. Duncan

Research output: Contribution to journalArticle

30 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)86-110
Number of pages25
JournalMechanisms of Development
Volume131
Issue number1
DOIs
StatePublished - Feb 2014

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Keywords

  • Ectodermal cell fate
  • Lens development
  • Sip1
  • Zeb2

ASJC Scopus subject areas

  • Developmental Biology
  • Embryology

Cite this

Manthey, A. L., Lachke, S. A., FitzGerald, P. G., Mason, R. W., Scheiblin, D. A., McDonald, J. H., & Duncan, M. K. (2014). Loss of Sip1 leads to migration defects and retention of ectodermal markers during lens development. Mechanisms of Development, 131(1), 86-110. https://doi.org/10.1016/j.mod.2013.09.005