Distinct roles for N-Cadherin linked c-Src and fyn kinases in lens development.
BACKGROUND
Src family tyrosine kinases (SFKs) are often coincidently expressed but few studies have dissected their individual functions in the same cell during development. Using the classical embryonic lens as our model, we investigated SFK signaling in the regulation of both differentiation initiation and morphogenesis, and the distinct functions of c-Src and Fyn in these processes.


RESULTS
Blocking SFK activity with the highly specific inhibitor PP1 induced initiation of the lens differentiation program but blocked lens fiber cell elongation and organization into mini lens-like structures called lentoids. These dichotomous roles for SFK signaling were discovered to reflect distinct functions of c-Src and Fyn and their differentiation-state-specific recruitment to and action at N-cadherin junctions. c-Src was highly associated with the nascent N-cadherin junctions of undifferentiated lens epithelial cells. Its siRNA knockdown promoted N-cadherin junctional maturation, blocked proliferation, and induced lens cell differentiation. In contrast, Fyn was recruited to mature N-cadherin junctions of differentiating lens cells and siRNA knockdown suppressed differentiation-specific gene expression and blocked morphogenesis.


CONCLUSIONS
Through inhibition of N-cadherin junction maturation, c-Src promotes lens epithelial cell proliferation and the maintenance of the lens epithelial cell undifferentiated state, while Fyn, signaling downstream of mature N-cadherin junctions, promotes lens fiber cell morphogenesis.
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Michelle
M
Leonard
Liping
L
Zhang
Brigid M
BM
Bleaken
A Sue
AS
Menko
D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D015820:Cadherins / Q000378:metabolism*; D002478:Cells, Cultured; D002642:Chick Embryo; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D007908:Lens, Crystalline / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D008954:Models, Biological; D038081:Organogenesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D051076:Proto-Oncogene Proteins c-fyn / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011784:Quail / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D015820:Cadherins; D034741:RNA, Small Interfering; D000081247:CSK Tyrosine-Protein Kinase; D051076:Proto-Oncogene Proteins c-fyn; D019061:src-Family Kinases