Integrin alpha4beta1 function is required for cell survival in developing retina.
In the retina, integrins in the beta1 family have been shown to be important in many phases of neuronal development, particularly neuroblast migration and axon outgrowth. However, the functions of specific integrin heterodimers are not well defined. In this study, we investigated the functions of beta1 integrins in developing chicken retina by expression of a dominant-negative beta1A construct using a replication-competent retrovirus. Inhibition of integrins using this approach resulted in alteration of cell morphology and increased apoptosis, but did not preclude migration and axon elongation. In an attempt to identify which specific beta1 heterodimer was important, expression and function of the alpha4beta1 heterodimer were also investigated. At early developmental stages, alpha4 protein and mRNA were detected in undifferentiated neuroblasts throughout the retina. At later stages, expression was confined to retinal ganglion cells (RGCs) and amacrine cells. A small molecule antagonist of alpha4 integrins was shown to inhibit neurite outgrowth on recombinant soluble vascular cell adhesion molecule-1 (VCAM-1), a known ligand of alpha4beta1. Introduction of alpha4 antagonist in vivo gave rise to increased apoptosis and led to a thinning of the retina and reduced numbers of retinal ganglion cells (RGCs). We conclude that the integrin alpha4beta1 is important for survival of developing retinal neurons, including RGCs.
Leu
Sergiu T
ST
Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, CA 93106, USA.
Jacques
Susan A L
SA
Wingerd
Kevin L
KL
Hikita
Sherry T
ST
Tolhurst
Erin C
EC
Pring
Jan L
JL
Wiswell
Derek
D
Kinney
Lisa
L
Goodman
Nichol L
NL
Jackson
David Y
DY
Clegg
Dennis O
DO
D000818:Animals; D017209:Apoptosis; D048430:Cell Shape; D002470:Cell Survival; D002642:Chick Embryo; D005822:Genetic Vectors; D006801:Humans; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000502:physiology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000166:cytology* / Q000196:embryology* / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D039041:Integrin alpha4beta1; D021122:Protein Subunits; D019010:Vascular Cell Adhesion Molecule-1