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