The Role of the HECT-Type Ubiquitin Ligases WWP1 and WWP2 in Nerve Cell Development and Function
Year: 2012
Type: dissertation
Abstract: Posttranscriptional modification of proteins through the ubiquitin pathway has recently emerged as an essential regulatory mechanism controlling neuronal development and function. WW domain-containing protein-1 and -2 (WWP1 and WWP2) are evolutionarily conserved HECT type E3 ubiquitin ligases in eukaryotes, and the C. elegans ortholog of WWP1/2 plays key roles in neuronal functions such as axon guidance and synaptic transmission. In the mammalian brain, however, the functions of WWP1/2 have never been explored and their substrates are unknown. In this study, I discovered a novel function of mammalian WWP1/2 in the developing brain. In analyses of brain specific conditional WWP1/2 deficient mice in vivo and in vitro, I found that WWP1/2 are critical for the establishment of neuronal polarity - the specification of a single axon and multiple dendrites, which is an essential step during neuronal development. I also show that SAD-A kinase, which is required for neuronal polarization in the cerebral cortex, is ubiquitinated by WWP1/2. Thus I propose that WWP1/2 contribute to neuronal polarization, probably by regulating the SAD kinase signaling pathway. Furthermore, I screened for binding proteins of WWP1/2 in the brain and identified WWP1/2 as specific E3 ligases for the synaptic scaffold proteins liprin-α3 and shank1a. These findings are consistent with the synaptic localization of WWP1/2 in mature neurons and indicate that WWP1/2 may be involved in synaptic transmission and synaptogenesis. Together, my findings show that WWP1/2 plays multiple roles in neuronal development and synaptic function in the mammalian brain.
Author: Kishimoto-Suga, Mika
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4212812114