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