Focal Manipulation of αE-catenin Function in the Developing Neocortex
Problems in neuronal cell proliferation and differentiation have been implicated in disorders such as microcephaly, mental retardation, and schizophrenia, while mis-regulated cell proliferation can lead to cortical malformations and epilepsy. Other diseases, such as Alzheimer's Disease, are characterized by synaptic dysfunction and increased neuronal cell death.
| Further insight into the development of many of these diseases
may be gained through understanding
the fundamental mechanisms regulating neuronal development. Neuronal proliferation, differentiation, and death often utilize similar cellular signaling cascades and components. Cadherin mediated adhesion and canonical wnt signaling are two important pathways that help regulate neuronal fate specification, cell survival, and neuronal synaptic architecture. β-catenin has been an intriguing target for experimental manipulation as it participates both of these cascades. In addition to β-catenin, alternative targets within both pathways have been characterized and perturbed to examine these cellular processes. An appealing target in cadherin mediated adhesion was α-catenin; classically thought to link the cadherin-catenin complex to the actin cytoskeleton. Recent empirical research has shown that though α-catenin is vital to adhesion, it is not merely a static linker protein but rather part of a dynamic adhesion complex. This accompanies a growing body of evidence suggesting additional non-adhesive functions for α-catenin. Intriguingly several different laboratories have demonstrated an interaction between α-catenin and β-catenin independent of adhesion, in different cellular systems, in vitro. However there is currently no in vivo evidence of the proposed relationship between α-catenin and wnt signaling. The additional functions of α-catenin are likely to be contextually and temporally specific. Moreover, a refined in vivo investigation of α-catenin’s non-adhesive functions has yet to be thoroughly pursued in mammalian systems. We are currently examining the role αE-catenin plays in proliferation and differentiation in the developing neocortex, particularly through its interaction with β-catenin mediated wnt signaling. To address this question in vivo, we are creating focal areas of altered function within the context of a wild type cortex using in utero electroporation. Click here to visit the Chenn Laboratory web site |
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