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EnglishThe 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 ADAM 10 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 ADAM 10 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.
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| Titolo: | An evolutionary recent neuroepithelial cell adhesion function of huntingtin implicates ADAM10-Ncadherin. |
| Autori: | Lo Sardo, V; Zuccato, C; Gaudenzi, G; Vitali, B; Ramos, C; Tartari, M; Myre, Ma; Walker, Ja; Pistocchi, A; Conti, Luciano; Valenza, M; Drung, B; Schmidt, B; Gusella, J; Zeitlin, S; Cotelli, F; Cattaneo, E. |
| Autori Unitn: | |
| Titolo del periodico: | NATURE NEUROSCIENCE |
| Anno di pubblicazione: | 2012 |
| Numero e parte del fascicolo: | 5 |
| Codice identificativo Scopus: | 2-s2.0-84860294838 |
| Codice identificativo Pubmed: | 22466506 |
| Codice identificativo ISI: | WOS:000303270200015 |
| Digital Object Identifier (DOI): | http://dx.doi.org/10.1038/nn.3080 |
| Handle: | http://hdl.handle.net/11572/99122 |
| Appare nelle tipologie: | 03.1 Articolo su rivista (Journal article) |
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