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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ADAM Proteins / antagonists & inhibitors
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ADAM Proteins / genetics
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ADAM Proteins / metabolism*
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ADAM10 Protein
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Amyloid Precursor Protein Secretases / antagonists & inhibitors
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Amyloid Precursor Protein Secretases / genetics
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Amyloid Precursor Protein Secretases / metabolism*
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Analysis of Variance
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Animals
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Animals, Genetically Modified
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Apoptosis / drug effects
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Apoptosis / genetics
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Biological Evolution*
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Body Patterning / drug effects
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Body Patterning / genetics
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Brain / cytology
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Brain / drug effects
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Brain / embryology
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Brain / metabolism
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Cadherins / genetics
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Cadherins / metabolism*
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Cell Adhesion / drug effects
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Cell Adhesion / physiology*
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Cell Differentiation / drug effects
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Cell Differentiation / genetics
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Cells, Cultured
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Cerebral Ventricles / cytology
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Cerebral Ventricles / embryology
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Dictyostelium
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Dipeptides / pharmacology
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Discs Large Homolog 1 Protein
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Drosophila melanogaster
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Embryo, Mammalian
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Embryo, Nonmammalian
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Embryonic Stem Cells / drug effects
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Embryonic Stem Cells / metabolism
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Gene Expression Regulation, Developmental / drug effects
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Gene Expression Regulation, Developmental / genetics
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / metabolism
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Guanylate Kinases / genetics
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Guanylate Kinases / metabolism
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Hedgehog Proteins / genetics
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Hedgehog Proteins / metabolism
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Huntingtin Protein
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Hydroxamic Acids / pharmacology
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Immunoprecipitation
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Intermediate Filament Proteins / genetics
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Membrane Proteins / antagonists & inhibitors
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Morpholines / pharmacology
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Mutation / genetics
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NFI Transcription Factors / metabolism
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Nestin
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Neuroepithelial Cells / drug effects
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Neuroepithelial Cells / physiology*
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Neurons / drug effects
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Neurons / physiology*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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PAX2 Transcription Factor / genetics
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PAX2 Transcription Factor / metabolism
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RNA, Small Interfering / genetics
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Tissue Inhibitor of Metalloproteinase-1 / pharmacology
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Transfection
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Wnt1 Protein / genetics
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Wnt1 Protein / metabolism
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Zebrafish / embryology
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Zebrafish Proteins / genetics
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Zebrafish Proteins / metabolism
Substances
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3-(formylhydroxyamino)-2-(3-phenyl-1-propyl)butanoic acid (2,2-dimethyl-1-methylcarbamoyl-1-propyl)amide
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CTF-1 transcription factor
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Cadherins
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Cdh2 protein, mouse
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Dipeptides
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Discs Large Homolog 1 Protein
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Dlg1 protein, mouse
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Hedgehog Proteins
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Htt protein, mouse
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Huntingtin Protein
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Hydroxamic Acids
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Intermediate Filament Proteins
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Membrane Proteins
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Morpholines
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NFI Transcription Factors
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Nerve Tissue Proteins
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Nes protein, mouse
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Nestin
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Nuclear Proteins
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PAX2 Transcription Factor
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RNA, Small Interfering
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Shha protein, zebrafish
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Tissue Inhibitor of Metalloproteinase-1
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Wnt1 Protein
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Zebrafish Proteins
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enhanced green fluorescent protein
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pax2a protein, zebrafish
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Green Fluorescent Proteins
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Guanylate Kinases
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Amyloid Precursor Protein Secretases
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ADAM Proteins
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ADAM10 Protein
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Adam10 protein, mouse