Alternative splicing modulates Disabled-1 (Dab1) function in the developing chick retina.
The Reelin-Disabled 1 (Dab1)-signaling pathway plays a critical role in neuronal cell positioning in the brain. We have isolated two alternatively spliced variants of Dab1 from chick retina, an early form (chDab1-E) expressed in undifferentiated cells and a late form (chDab1-L) expressed in amacrine and ganglion cells. A key difference between the two forms is the exclusion in chDab1-E of two Src-related tyrosine kinase recognition sites implicated in Reelin-mediated Dab1 tyrosine phosphorylation. Retinal cultures transfected with a chDab1-L expression construct undergo a dramatic change in morphology, accompanied by the formation of numerous thin elongated processes, increased tyrosine phosphorylation, activation of Src family kinase(s) and increased levels of the axonal outgrowth protein growth-associated protein-43. In contrast, chDab1-E transfectants retain an undifferentiated morphology. Mutational analysis implicates a specific tyrosine (tyr-198) in the morphological and biochemical alterations associated with chDab1-L expression. We propose that alternative splicing of chDab1 represents an effective and flexible way of regulating the Reelin-Dab1-signaling pathway in a mixed cell population, by ensuring that secreted Reelin activates the signaling cascade only in target neuronal cells.
Katyal
Sachin
S
Department of Oncology, Cross Cancer Institute, University of Alberta, Alberta, Canada.
Godbout
Roseline
R
D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D002645:Chickens; D018076:DNA, Complementary / Q000235:genetics; D004789:Enzyme Activation; D019922:GAP-43 Protein / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D012160:Retina / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D019061:src-Family Kinases / Q000378:metabolism
D018076:DNA, Complementary; D019922:GAP-43 Protein; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D019000:Phosphotyrosine; D019061:src-Family Kinases