title: The Dkk1 dose is critical for eye development.
abstract: During mammalian ocular development, several signaling pathways control the spatiotemporal highly defined realization of the three-dimensional eye architecture. Given the complexity of these inductive signals, the developing eye is a sensitive organ for several diseases. In this study, we investigated a Dkk1+/- haploinsufficiency during eye development, resulting in coloboma and anterior eye defects, two common developmental eye disorders. Dkk1 impacts eye development from a defined developmental time point on, and is critical for lens separation from the surface ectoderm via β-catenin mediated Pdgfrα and E-cadherin expression. Dkk1 does not impact the dorso ventral retina patterning in general but is critical for Shh dependent Pax2 extension into the midline region. The described results also indicate that the retinal Dkk1 dose is critical for important steps during eye development, such as optic fissure closure and cornea formation. Further analysis of the relationship between Dkk1 and Shh signaling revealed that Dkk1 and Shh coordinatively control anterior head formation and eye induction. During eye development itself, retinal Dkk1 activation is depending on cilia mediated Gli3 regulation. Therefore, our data essentially improve the knowledge of coloboma and anterior eye defects, which are common human eye developmental defects.
authors.affiliation: Institute for Animal Developmental, Molecular Biology, Heinrich-Heine-University, Düsseldorf, Germany. Oliver.Lieven@med.lu.se
authors.forename: Oliver
authors.initials: O
authors.lastname: Lieven
authors.forename: Ulrich
authors.initials: U
authors.lastname: Rüther
mesh_terms: D000818:Animals; D015820:Cadherins / Q000096:biosynthesis; D003103:Coloboma / Q000235:genetics / Q000503:physiopathology; D004195:Disease Models, Animal; D004475:Ectoderm / Q000254:growth & development / Q000503:physiopathology; D005123:Eye / Q000254:growth & development*; D005124:Eye Abnormalities / Q000235:genetics / Q000503:physiopathology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D057895:Haploinsufficiency; D053823:Hedgehog Proteins / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D051741:Kruppel-Like Transcription Factors / Q000502:physiology; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000502:physiology; D051762:PAX2 Transcription Factor / Q000502:physiology; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000096:biosynthesis; D000074290:Zinc Finger Protein Gli3; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015820:Cadherins; C501127:Dkk1 protein, mouse; C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D051762:PAX2 Transcription Factor; C497319:Pax2 protein, mouse; C465570:Shh protein, mouse; D000074290:Zinc Finger Protein Gli3; D051176:beta Catenin; D020796:Receptor, Platelet-Derived Growth Factor alpha