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