title: Loss of MAP3K1 enhances proliferation and apoptosis during retinal development.
abstract: Precise coordination of progenitor cell proliferation and differentiation is essential for proper organ morphogenesis and function during mammalian development. The mitogen-activated protein kinase kinase kinase 1 (MAP3K1) has a well-established role in anterior eyelid development, as Map3k1-knockout mice have defective embryonic eyelid closure and an `eye-open at birth' (EOB) phenotype. Here, we show that MAP3K1 is highly expressed in the posterior of the developing eye and is required for retina development. The MAP3K1-deficient mice exhibit increased proliferation and apoptosis, and Müller glial cell overproduction in the developing retinas. Consequently, the retinas of these mice show localized rosette-like arrangements in the outer nuclear layer, and develop abnormal vascularization, broken down retinal pigment epithelium, photoreceptor loss and early onset of retinal degeneration. Although the retinal defect is associated with increased cyclin D1 and CDK4/6 expression, and RB phosphorylation and E2F-target gene upregulation, it is independent of the EOB phenotype and of JNK. The retinal developmental defect still occurs in knockout mice that have undergone tarsorrhaphy, but is absent in compound mutant Map3k1(+/ΔKD)Jnk1(-/-) and Map3k1(+/ΔKD)Jnk(+/-)Jnk2(+/-) mice that have EOB and reduced JNK signaling. Our results unveil a novel role for MAP3K1 in which it crosstalks with the cell cycle regulatory pathways in the prevention of retina malformation and degeneration.
authors.affiliation: Department of Environmental Health, University of Cincinnati, College of Medicine, Cincinnati, OH 45267-0056, USA.
authors.forename: Maureen
authors.initials: M
authors.lastname: Mongan
authors.forename: Jingcai
authors.initials: J
authors.lastname: Wang
authors.forename: Hongshan
authors.initials: H
authors.lastname: Liu
authors.forename: Yunxia
authors.initials: Y
authors.lastname: Fan
authors.forename: Chang
authors.initials: C
authors.lastname: Jin
authors.forename: Winston Y-W
authors.initials: WY
authors.lastname: Kao
authors.forename: Ying
authors.initials: Y
authors.lastname: Xia
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics*; D049109:Cell Proliferation; D004622:Embryo, Mammalian; D005123:Eye / Q000254:growth & development / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D055786:Gene Knockout Techniques; D048728:MAP Kinase Kinase Kinase 1 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D013508:Ophthalmologic Surgical Procedures; D012160:Retina / Q000196:embryology / Q000254:growth & development* / Q000378:metabolism / Q000601:surgery; D013537:Sutures
chemical_list: D048728:MAP Kinase Kinase Kinase 1; C482578:Map3k1 protein, mouse