title: The type I BMP receptors, Bmpr1a and Acvr1, activate multiple signaling pathways to regulate lens formation.
abstract: BMPs play multiple roles in development and BMP signaling is essential for lens formation. However, the mechanisms by which BMP receptors function in vertebrate development are incompletely understood. To determine the downstream effectors of BMP signaling and their functions in the ectoderm that will form the lens, we deleted the genes encoding the type I BMP receptors, Bmpr1a and Acvr1, and the canonical transducers of BMP signaling, Smad4, Smad1 and Smad5. Bmpr1a and Acvr1 regulated cell survival and proliferation, respectively. Absence of both receptors interfered with the expression of proteins involved in normal lens development and prevented lens formation, demonstrating that BMPs induce lens formation by acting directly on the prospective lens ectoderm. Remarkably, the canonical Smad signaling pathway was not needed for most of these processes. Lens formation, placode cell proliferation, the expression of FoxE3, a lens-specific transcription factor, and the lens protein, alphaA-crystallin were regulated by BMP receptors in a Smad-independent manner. Placode cell survival was promoted by R-Smad signaling, but in a manner that did not involve Smad4. Of the responses tested, only maintaining a high level of Sox2 protein, a transcription factor expressed early in placode formation, required the canonical Smad pathway. A key function of Smad-independent BMP receptor signaling may be reorganization of actin cytoskeleton to drive lens invagination.
authors.affiliation: Departments of Ophthalmology and Visual Sciences, Washington University, St. Louis, MO 63110, USA.
authors.forename: Ramya
authors.initials: R
authors.lastname: Rajagopal
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Dattilo
authors.forename: Vesa
authors.initials: V
authors.lastname: Kaartinen
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishina
authors.forename: Chu-Xia
authors.initials: CX
authors.lastname: Deng
authors.forename: Lieve
authors.initials: L
authors.lastname: Umans
authors.forename: An
authors.initials: A
authors.lastname: Zwijsen
authors.forename: Anita B
authors.initials: AB
authors.lastname: Roberts
authors.forename: David C
authors.initials: DC
authors.lastname: Beebe
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics / Q000502:physiology*; D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D002470:Cell Survival; D007908:Lens, Crystalline / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins / Q000502:physiology
chemical_list: D051785:Smad Proteins; D030201:Activin Receptors, Type I; C498943:Acvr1 protein, mouse; C498212:Bmpr1a protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I