Abstract
Signaling downstream of receptor tyrosine kinases controls cell differentiation and survival. How signals from different receptors are integrated is, however, still poorly understood. In this work, we have identified Kidins220 (Kinase D interacting substrate of 220 kDa)/ARMS (Ankyrin repeat-rich membrane spanning) as a main player in the modulation of neurotrophin and vascular endothelial growth factor (VEGF) signaling in vivo, and a primary determinant for neuronal and cardiovascular development. Kidins220−/− embryos die at late stages of gestation, and show extensive cell death in the central and peripheral nervous systems. Primary neurons from Kidins220−/− mice exhibit reduced responsiveness to brain-derived neurotrophic factor, in terms of activation of mitogen-activated protein kinase signaling, neurite outgrowth and potentiation of excitatory postsynaptic currents. In addition, mice lacking Kidins220 display striking cardiovascular abnormalities, possibly due to impaired VEGF signaling. In support of this hypothesis, we demonstrate that Kidins220 constitutively interacts with VEGFR2. These findings, together with the data presented in the accompanying paper, indicate that Kidins220 mediates the integration of several growth factor receptor pathways during development, and mediates the activation of distinct downstream cascades according to the location and timing of stimulation.
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Abbreviations
- BDNF:
-
brain-derived neurotrophic factor
- CNS:
-
central nervous system
- DIV:
-
days in vitro
- DRG:
-
dorsal root ganglia
- EPSC:
-
excitatory postsynaptic current
- ES:
-
embryonic stem
- Kidins220/ARMS:
-
kinase D interacting substrate of 220 kDa/ankyrin repeat-rich membrane spanning
- MAPK/Erk:
-
mitogen-activated protein kinase/extracellular signal-activated kinase
- MN:
-
motor neuron
- NGF:
-
nerve growth factor
- Nrp1:
-
neuropilin-1
- NT:
-
neurotrophin
- p75NTR:
-
p75 neurotrophin receptor
- PNS:
-
peripheral nervous system
- Trk:
-
tropomyosin-related kinase receptor
- VEGF:
-
vascular endothelial growth factor
- VEGFR:
-
vascular endothelial growth factor receptor
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Acknowledgements
We thank J Storm-Mathisen for help with the anatomical analysis, F Succol and M Nanni for technical assistance with primary neuronal cultures, C Ruhrberg for help with the analysis of Nrp1−/−-like phenotypes, G Kelly for statistical analysis, A Weston and T Arnett for microCT, N Corps for the CTAn software and scanning, CL Thomas for critical reading of the manuscript and members of the Molecular Neuropathobiology laboratory for helpful discussion. This study was supported by research grants from: Cancer Research UK (FC, AY, BS-D and GS); the Italian Institute of Technology (FC, JS-S, PB and FB); the Italian Ministry of University and Research (FB and PB); the Italian Ministry of Health Progetto Giovani (PB); the Compagnia di San Paolo, Torino (FB, PB); Telethon-Italy (Grant GGP09134 to FB and GGP09066 to PB); BBSRC (MAQ and MK).
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Companion paper of: doi:10.1038/cddis.2011.108
Supplementary Information accompanies the paper on Cell Death and Differentiation website
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Cesca, F., Yabe, A., Spencer-Dene, B. et al. Kidins220/ARMS mediates the integration of the neurotrophin and VEGF pathways in the vascular and nervous systems. Cell Death Differ 19, 194–208 (2012). https://doi.org/10.1038/cdd.2011.141
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DOI: https://doi.org/10.1038/cdd.2011.141
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