The canonical Wnt signaling antagonist DKK2 is an essential effector of PITX2 function during normal eye development.
Local control of cell signaling activity and integration of inputs from multiple signaling pathways are central for normal development but the underlying mechanisms remain poorly understood. Here we show that Dkk2, encoding an antagonist of canonical Wnt signaling, is an essential downstream target of the PITX2 homeodomain transcription factor in neural crest during eye development. Canonical Wnt signaling is ectopically activated in central ocular surface ectoderm and underlying mesenchyme in Pitx2- and Dkk2-deficient mice. General ocular surface ectoderm identity is maintained during development in Dkk2-deficient mice but peripheral fates, including conjunctival goblet cells and eyelash follicles, are ectopically permitted within more central structures and eyelids are hypomorphic. Loss of DKK2 results in ectopic blood vessels within the periocular mesenchyme and PITX2 expression remains persistently high, providing evidence for a negative feedback loop. Collectively, these data suggest that activation of Dkk2 by PITX2 provides a mechanism to locally suppress canonical Wnt signaling activity during eye development, a paradigm that may be a model for achieving local or transient inhibition of pathway activity elsewhere during embryogenesis. We further propose a model placing PITX2 as an essential integration node between retinoic acid and canonical Wnt signaling during eye development.
Gage
Philip J
PJ
Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor, MI 48105, USA. philgage@umich.edu
Qian
Min
M
Wu
Dianqing
D
Rosenberg
Kevin I
KI
D000818:Animals; D003228:Conjunctiva / Q000196:embryology; D003315:Cornea / Q000196:embryology; D005123:Eye / Q000196:embryology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D009154:Mutation; D009432:Neural Crest / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D051153:Wnt Proteins / Q000378:metabolism; D000097577:Homeobox Protein PITX2
D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D014157:Transcription Factors; D051153:Wnt Proteins; D000097577:Homeobox Protein PITX2; C405060:Dkk2 protein, mouse; C112890:Foxc1 protein, mouse; C082078:mesenchyme fork head 1 protein