title: Prox1 and fibroblast growth factor receptors form a novel regulatory loop controlling lens fiber differentiation and gene expression.
abstract: Lens epithelial cells differentiate into lens fibers (LFs) in response to a fibroblast growth factor (FGF) gradient. This cell fate decision requires the transcription factor Prox1, which has been hypothesized to promote cell cycle exit in differentiating LF cells. However, we find that conditional deletion of Prox1 from mouse lenses results in a failure in LF differentiation despite maintenance of normal cell cycle exit. Instead, RNA-seq demonstrated that Prox1 functions as a global regulator of LF cell gene expression. Intriguingly, Prox1 also controls the expression of fibroblast growth factor receptors (FGFRs) and can bind to their promoters, correlating with decreased downstream signaling through MAPK and AKT in Prox1 mutant lenses. Further, culturing rat lens explants in FGF increased their expression of Prox1, and this was attenuated by the addition of inhibitors of MAPK. Together, these results describe a novel feedback loop required for lens differentiation and morphogenesis, whereby Prox1 and FGFR signaling interact to mediate LF differentiation in response to FGF.
authors.affiliation: Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA.
authors.forename: Dylan S
authors.initials: DS
authors.lastname: Audette
authors.affiliation: Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA.
authors.forename: Deepti
authors.initials: D
authors.lastname: Anand
authors.affiliation: Discipline of Anatomy & Histology, Bosch Institute & Save Sight Institute, University of Sydney, Sydney, New South Wales 2000, Australia.
authors.forename: Tammy
authors.initials: T
authors.lastname: So
authors.affiliation: Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA.
authors.forename: Troy B
authors.initials: TB
authors.lastname: Rubenstein
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: Discipline of Anatomy & Histology, Bosch Institute & Save Sight Institute, University of Sydney, Sydney, New South Wales 2000, Australia.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Lovicu
authors.affiliation: Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA duncanm@udel.edu.
authors.forename: Melinda K
authors.initials: MK
authors.lastname: Duncan
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007908:Lens, Crystalline / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D018398:Homeodomain Proteins; D017468:Receptors, Fibroblast Growth Factor; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein; D005346:Fibroblast Growth Factors
keywords: Lens; Morphogenesis; Regulatory loop