PUBLICATION

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
  • Morpholines/pharmacology
  • ADAM Proteins/antagonists & inhibitors
  • ADAM Proteins/genetics
  • ADAM Proteins/metabolism*
  • Tissue Inhibitor of Metalloproteinase-1/pharmacology
  • RNA, Small Interfering/genetics
  • NFI Transcription Factors/metabolism
  • Animals
  • Apoptosis/drug effects
  • Apoptosis/genetics
  • Embryo, Nonmammalian
  • Cells, Cultured
  • Embryonic Stem Cells/drug effects
  • Embryonic Stem Cells/metabolism
  • Analysis of Variance
  • Hydroxamic Acids/pharmacology
  • Hedgehog Proteins/genetics
  • Hedgehog Proteins/metabolism
  • Amyloid Precursor Protein Secretases/antagonists & inhibitors
  • Amyloid Precursor Protein Secretases/genetics
  • Amyloid Precursor Protein Secretases/metabolism*
  • Gene Expression Regulation, Developmental/drug effects
  • Gene Expression Regulation, Developmental/genetics
  • Wnt1 Protein/genetics
  • Wnt1 Protein/metabolism
  • Embryo, Mammalian
  • Dipeptides/pharmacology
  • Biological Evolution*
  • Cerebral Ventricles/cytology
  • Cerebral Ventricles/embryology
  • Neurons/drug effects
  • Neurons/physiology*
  • Cadherins/genetics
  • Cadherins/metabolism*
  • Nuclear Proteins/genetics
  • Nuclear Proteins/metabolism*
  • Brain/cytology
  • Brain/drug effects
  • Brain/embryology
  • Brain/metabolism
  • Cell Differentiation/drug effects
  • Cell Differentiation/genetics
  • Cell Adhesion/drug effects
  • Cell Adhesion/physiology*
  • Intermediate Filament Proteins/genetics
  • Zebrafish/embryology
  • Guanylate Kinases/genetics
  • Guanylate Kinases/metabolism
  • Mutation/genetics
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
  • Nestin
  • Immunoprecipitation
  • Animals, Genetically Modified
  • Dictyostelium
  • Neuroepithelial Cells/drug effects
  • Neuroepithelial Cells/physiology*
  • Green Fluorescent Proteins/genetics
  • Green Fluorescent Proteins/metabolism
  • Drosophila melanogaster
  • Mice
  • Body Patterning/drug effects
  • Body Patterning/genetics
  • Membrane Proteins/antagonists & inhibitors
  • Membrane Proteins/genetics
  • Membrane Proteins/metabolism*
  • Transfection
  • PAX2 Transcription Factor/genetics
  • PAX2 Transcription Factor/metabolism
  • Nerve Tissue Proteins/genetics
  • Nerve Tissue Proteins/metabolism*
(all 71)
PubMed
22466506 Full text @ Nat. Neurosci.
Abstract

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.

Genes / Markers
Figures
No images available
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping