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