Essential Roles for the Abl and Arg Tyrosine Kinases in Neurulation

Abstract

The Abl and Arg tyrosine kinases play fundamental roles in the development and function of the central nervous system. Arg is most abundant in adult mouse brain, especially in synapse-rich regions. arg(-/-) mice develop normally but exhibit multiple behavioral abnormalities, suggesting that arg(-/-) brains suffer from defects in neuronal function. Embryos deficient in both Abl and Arg suffer from defects in neurulation and die before 11 days postcoitum (dpc). Although they divide normally, abl(-/-)arg(-/-) neuroepithelial cells display gross alterations in their actin cytoskeleton. We find that Abl and Arg colocalize with each other and with actin microfilaments at the apical surface of the developing neuroepithelium. Thus, Abl and Arg play essential roles in neurulation and can regulate the structure of the actin cytoskeleton.

Cycling, stressed-out and nervous: cellular functions of c-Abl

“…The subcellular location of c-Abl was first determined by overexpressing the murine type IV protein in fibroblasts and was unexpectedly found to be largely nuclear, but with a significant fraction in the cytoplasm that is associated mostly with filamentous actin and the plasma membrane 3 . This general pattern of localization of c-Abl has been confirmed in other cell types and for endogenous Abl, although it is apparent that, in some tissues, such as primary haematopoietic cells 4 and neurons 5 , c-Abl is more cytoplasmic than nuclear. Overexpression of the non-myristoylated type Ia/I form of c-Abl is very difficult, and, although its localization is assumed to be similar to the myristoylated form, this has not been demonstrated directly.…”

“…The facts that Abl can arrest cells in G1 and that Abl kinase activity is stimulated by IR suggest that Abl might play a role in the G1 arrest response to IR. A defect in the G1-S checkpoint response to IR in abl -/-fibroblasts has been reported 40 , but subsequent studies from several groups failed to detect such a defect 5,41 . Similarly, IR is a relatively weak inducer of JNK/SAPK activity, and there appears to be no defect in the modest level of JNK/SAPK activation in abl -/-fibroblasts in response to high doses of IR 41 .…”

“…2). Because cells lacking Abl or both Abl and the related Arg protein 5 do not seem to have obvious defects in DNA repair or cell-cycle progression, the role of c-Abl in these processes must be redundant, subtle, or both. Obviously, the precise role played by Abl in these complex cellular responses will require much more investigation.…”

“…There are some conflicting observations (see text). c-Abl has been reported to be required for ionizing radiation (IR)-induced G1 arrest and to be independent of p21 40 , while other observations suggest that it is not required 5,41 . A fraction of Atm might bind to Abl constitutively 35 , and c-Abl in S phase might be activated preferentially by IR 41 . trends in CELL BIOLOGY (Vol.…”

“…arg -/-mice develop normally but display several behavioural abnormalities, suggesting defects in neuronal function. However, embryos lacking both Abl and Arg die before embryonic day 11 with gross defects in the neural tube and disorganization of the neuroepithelial actin cytoskeleton 5 . Because the Arg protein is exclusively cytoplasmic, this suggests that Abl and Arg have redundant cytoplasmic functions in the embryonic CNS, and indeed the two kinases colocalize with each other and with actin microfilaments at the apical surface of the neuroepithelium.…”