An evolutionary recent neuroepithelial cell adhesion function of huntingtin implicates ADAM10-Ncadherin
- Authors
- Lo Sardo, V., Zuccato, C., Gaudenzi, G., Vitali, B., Ramos, C., Tartari, M., Myre, M.A., Walker, J.A., Pistocchi, A., Conti, L., Valenza, M., Drung, B., Schmidt, B., Gusella, J., Zeitlin, S., Cotelli, F., and Cattaneo, E.
- ID
- ZDB-PUB-120406-1
- Date
- 2012
- Source
- Nature Neuroscience 15(5): 713-721 (Journal)
- Registered Authors
- Cotelli, Franco
- Keywords
- none
- MeSH Terms
-
- Cell Adhesion/drug effects
- Cell Adhesion/physiology*
- NFI Transcription Factors/metabolism
- Embryonic Stem Cells/drug effects
- Embryonic Stem Cells/metabolism
- Brain/cytology
- Brain/drug effects
- Brain/embryology
- Brain/metabolism
- Dictyostelium
- Embryo, Mammalian
- Nestin
- Nerve Tissue Proteins/genetics
- Nerve Tissue Proteins/metabolism*
- Tissue Inhibitor of Metalloproteinase-1/pharmacology
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- Mice
- PAX2 Transcription Factor/genetics
- PAX2 Transcription Factor/metabolism
- Cells, Cultured
- Cadherins/genetics
- Cadherins/metabolism*
- Body Patterning/drug effects
- Body Patterning/genetics
- Drosophila melanogaster
- Biological Evolution*
- Green Fluorescent Proteins/genetics
- Green Fluorescent Proteins/metabolism
- Guanylate Kinases/genetics
- Guanylate Kinases/metabolism
- Embryo, Nonmammalian
- Cerebral Ventricles/cytology
- Cerebral Ventricles/embryology
- Neurons/drug effects
- Neurons/physiology*
- Intermediate Filament Proteins/genetics
- ADAM Proteins/antagonists & inhibitors
- ADAM Proteins/genetics
- ADAM Proteins/metabolism*
- Animals
- Hydroxamic Acids/pharmacology
- Neuroepithelial Cells/drug effects
- Neuroepithelial Cells/physiology*
- Hedgehog Proteins/genetics
- Hedgehog Proteins/metabolism
- Immunoprecipitation
- Amyloid Precursor Protein Secretases/antagonists & inhibitors
- Amyloid Precursor Protein Secretases/genetics
- Amyloid Precursor Protein Secretases/metabolism*
- Analysis of Variance
- Gene Expression Regulation, Developmental/drug effects
- Gene Expression Regulation, Developmental/genetics
- Apoptosis/drug effects
- Apoptosis/genetics
- Cell Differentiation/drug effects
- Cell Differentiation/genetics
- Morpholines/pharmacology
- Zebrafish/embryology
- Animals, Genetically Modified
- Membrane Proteins/antagonists & inhibitors
- Membrane Proteins/genetics
- Membrane Proteins/metabolism*
- Mutation/genetics
- Dipeptides/pharmacology
- Nuclear Proteins/genetics
- Nuclear Proteins/metabolism*
- Transfection
- RNA, Small Interfering/genetics
- Wnt1 Protein/genetics
- Wnt1 Protein/metabolism
- PubMed
- 22466506 Full text @ Nat. Neurosci.
The Huntington's disease gene product, huntingtin, is indispensable for neural tube formation, but its role is obscure. We studied neurulation in htt-null embryonic stem cells and htt-morpholino zebrafish embryos and found a previously unknown, evolutionarily recent function for this ancient protein. We found that htt was essential for homotypic interactions between neuroepithelial cells; it permitted neurulation and rosette formation by regulating metalloprotease ADAM10 activity and Ncadherin cleavage. This function was embedded in the N terminus of htt and was phenocopied by treatment of htt knockdown zebrafish with an ADAM10 inhibitor. Notably, in htt-null cells, reversion of the rosetteless phenotype occurred only with expression of evolutionarily recent htt heterologues from deuterostome organisms. Conversely, all of the heterologues that we tested, including htt from Drosophila melanogaster and Dictyostelium discoideum, exhibited anti-apoptotic activity. Thus, anti-apoptosis may have been one of htt's ancestral function(s), but, in deuterostomes, htt evolved to acquire a unique regulatory activity for controlling neural adhesion via ADAM10-Ncadherin, with implications for brain evolution and development.