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
-
- ADAM Proteins/antagonists & inhibitors
- ADAM Proteins/genetics
- ADAM Proteins/metabolism*
- Transfection
- Amyloid Precursor Protein Secretases/antagonists & inhibitors
- Amyloid Precursor Protein Secretases/genetics
- Amyloid Precursor Protein Secretases/metabolism*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- RNA, Small Interfering/genetics
- Immunoprecipitation
- Drosophila melanogaster
- Cadherins/genetics
- Cadherins/metabolism*
- Cells, Cultured
- Embryo, Mammalian
- Nerve Tissue Proteins/genetics
- Nerve Tissue Proteins/metabolism*
- Hydroxamic Acids/pharmacology
- Gene Expression Regulation, Developmental/drug effects
- Gene Expression Regulation, Developmental/genetics
- Animals, Genetically Modified
- Cell Adhesion/drug effects
- Cell Adhesion/physiology*
- Embryo, Nonmammalian
- Hedgehog Proteins/genetics
- Hedgehog Proteins/metabolism
- Analysis of Variance
- Morpholines/pharmacology
- Neurons/drug effects
- Neurons/physiology*
- Dipeptides/pharmacology
- Cerebral Ventricles/cytology
- Cerebral Ventricles/embryology
- Mice
- Embryonic Stem Cells/drug effects
- Embryonic Stem Cells/metabolism
- Nestin
- Cell Differentiation/drug effects
- Cell Differentiation/genetics
- Brain/cytology
- Brain/drug effects
- Brain/embryology
- Brain/metabolism
- Nuclear Proteins/genetics
- Nuclear Proteins/metabolism*
- Neuroepithelial Cells/drug effects
- Neuroepithelial Cells/physiology*
- Animals
- Dictyostelium
- Intermediate Filament Proteins/genetics
- Green Fluorescent Proteins/genetics
- Green Fluorescent Proteins/metabolism
- Zebrafish/embryology
- Guanylate Kinases/genetics
- Guanylate Kinases/metabolism
- Membrane Proteins/antagonists & inhibitors
- Membrane Proteins/genetics
- Membrane Proteins/metabolism*
- Wnt1 Protein/genetics
- Wnt1 Protein/metabolism
- Body Patterning/drug effects
- Body Patterning/genetics
- Tissue Inhibitor of Metalloproteinase-1/pharmacology
- Mutation/genetics
- PAX2 Transcription Factor/genetics
- PAX2 Transcription Factor/metabolism
- Apoptosis/drug effects
- Apoptosis/genetics
- Biological Evolution*
- NFI Transcription Factors/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.