Functional analysis of Kidins220/ARMS in vivo.
Doctoral thesis, UCL (University College London).
In this work, I studied the in vivo functions of Kidins220 (Kinase D-interacting substrate of 220kDa, also known as ARMS; ankyrin-repeat rich membrane spanning), by phenotypic analyses of full and conditional Kidins220 knockout mice. Kidins220 is a large transmembrane protein involved in neurotrophin and Eph/ephrin signalling, with roles in neurite outgrowth, neuroprotection, and synaptic modulation. I demonstrate pleiotropic functions of Kidins220 during development of the nervous and cardiovascular systems, and a novel function downstream of vascular endothelial growth factor (VEGF)/neuropilin-1 (Nrp1) pathway. Kidins220-/- embryos develop smaller than wildtype, and die around birth. Analysis of Kidins220-/- brains revealed increased apoptosis in specific brain regions. Increased apoptosis was also observed in the peripheral nervous system, suggesting that it mediates the survival of specific cell populations. Kidins220 also regulates proliferation in the cortex. Enlargement of the heart and outflow tract defects are observed in Kidins220-/- mice, suggesting its function in neural crest cells. In vitro experiments confirmed Kidins220 as mediating neurotrophic response. Vascular defects are also observed in Kidins220-/- brains. Glomeruloid vascular tufts formed in the Kidins220-/- brains are similar to that of Nrp1-/- mice. Nrp1 is a coreceptor to VEGF receptors and I observed that Kidins220 coimmunoprecipitates with VEGFR2 and VEGFR3. The presence of angiogenesis defects specifically in the brain point to the spatially and temporally restricted functions of Kidins220. In addition, I have also identified the presence of alternative splice isoforms of Kidins220 only found in the adult. The splicing will yield a shorter Kidins220 protein lacking many of its protein-protein interacting domains, suggesting that it plays a different function from that of the conventional Kidins220 isoform. This work therefore reports novel functions of Kidins220 during embryonic development, likely through its involvement in the neurotrophin, ephrin and VEGF receptor pathways, and novel splice isoforms of Kidins220.
|Title:||Functional analysis of Kidins220/ARMS in vivo|
|Additional information:||Permission for digitisation not received|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Life Sciences|
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