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