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