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