title: An evolutionary recent neuroepithelial cell adhesion function of  huntingtin implicates ADAM10-Ncadherin.
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.
authors.affiliation: Department of Pharmacological Sciences and Centre for Stem Cell Research, Università degli Studi di Milano, Milano, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Lo Sardo
authors.forename: Chiara
authors.initials: C
authors.lastname: Zuccato
authors.forename: Germano
authors.initials: G
authors.lastname: Gaudenzi
authors.forename: Barbara
authors.initials: B
authors.lastname: Vitali
authors.forename: Catarina
authors.initials: C
authors.lastname: Ramos
authors.forename: Marzia
authors.initials: M
authors.lastname: Tartari
authors.forename: Michael A
authors.initials: MA
authors.lastname: Myre
authors.forename: James A
authors.initials: JA
authors.lastname: Walker
authors.forename: Anna
authors.initials: A
authors.lastname: Pistocchi
authors.forename: Luciano
authors.initials: L
authors.lastname: Conti
authors.forename: Marta
authors.initials: M
authors.lastname: Valenza
authors.forename: Binia
authors.initials: B
authors.lastname: Drung
authors.forename: Boris
authors.initials: B
authors.lastname: Schmidt
authors.forename: James
authors.initials: J
authors.lastname: Gusella
authors.forename: Scott
authors.initials: S
authors.lastname: Zeitlin
authors.forename: Franco
authors.initials: F
authors.lastname: Cotelli
authors.forename: Elena
authors.initials: E
authors.lastname: Cattaneo
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D005075:Biological Evolution; D019521:Body Patterning / Q000187:drug effects / Q000235:genetics; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002552:Cerebral Ventricles / Q000166:cytology / Q000196:embryology; D004023:Dictyostelium; D004151:Dipeptides / Q000494:pharmacology; D000074288:Discs Large Homolog 1 Protein; D004331:Drosophila melanogaster; D004622:Embryo, Mammalian; D004625:Embryo, Nonmammalian; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D051528:Guanylate Kinases / Q000235:genetics / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D000071058:Huntingtin Protein; D006877:Hydroxamic Acids / Q000494:pharmacology; D047468:Immunoprecipitation; D007381:Intermediate Filament Proteins / Q000235:genetics; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D051839:NFI Transcription Factors / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D064231:Nestin; D046569:Neuroepithelial Cells / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D051762:PAX2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000494:pharmacology; D014162:Transfection; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C555398:3-(formylhydroxyamino)-2-(3-phenyl-1-propyl)butanoic acid (2,2-dimethyl-1-methylcarbamoyl-1-propyl)amide; C077305:CTF-1 transcription factor; D015820:Cadherins; C489083:Cdh2 protein, mouse; D004151:Dipeptides; D000074288:Discs Large Homolog 1 Protein; C000614189:Dlg1 protein, mouse; D053823:Hedgehog Proteins; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D006877:Hydroxamic Acids; D007381:Intermediate Filament Proteins; D008565:Membrane Proteins; D009025:Morpholines; D051839:NFI Transcription Factors; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D009687:Nuclear Proteins; D051762:PAX2 Transcription Factor; D034741:RNA, Small Interfering; C524053:Shha protein, zebrafish; D019715:Tissue Inhibitor of Metalloproteinase-1; D051155:Wnt1 Protein; D029961:Zebrafish Proteins; C485184:enhanced green fluorescent protein; C497320:pax2a protein, zebrafish; D049452:Green Fluorescent Proteins; D051528:Guanylate Kinases; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse