NEURAL ROSETTES FORMATION AS A NEWLY EMERGENT HUNTINGTIN FUNCTION

Huntingtin is a large, ubiquitous, partially unknown protein, in which mutation in its N-terminus is the cause of genetic, neurodegenerative disease called Huntington Disease. Although the presence of mutated huntingtin, from one decade it is known that the loss of wild-type protein can contribute to pathogenesis of HD (Cattaneo et al 2000). Huntingtin is embryonic lethal during embryogenesis and it exerts a fundamental role in the adult brain as a protein sustaining viability and health of mature neurons. Huntingtin is shown to be involved in neuron viability and maintenance, but its really and univocal function is already unknown. This study, object of my PhD project is focused on understand normal huntingtin function. Firstly, through a bioinformatic study by multialignment of 17 different homologues of huntingtin, both in deuterostome and protostome branches, we dissect the primary aminoacid sequence of huntingtin to reveal the presence of protein domains. The C-terminal portion of the protein proved to be conserved during evolution, while the N-terminal tract exhibited more recent evolution of the sequence. Moreover, look at the particular evolution and specification of the nervous system structures, and complexity along deuterostomes, we speculate that the evolution of the primary huntingtin aminoacid sequence parallels the particular evolution of the nervous system. In this view huntingtin could have evolved during phylogenesis a particular neural function. Furthermore, we study the role of normal huntingtin since its early embryonic function, in particular during the early phases of neural development, by using embryonic stem cell model. To dissect how this function is acquired during phylogenesis we choose to study neural differentiation process and the activity of the N-terminal domain during neurulation. We demonstrated that: i) huntingtin has a key role in the formation of neural tube-like rosettes, since its absence lead to a severe disorganization of neural precursors cells. ii) This defect is due to an impaired cell-cell adhesion mechanism, mediated by N-cadherin. iii) This function has emerged during deuterostomes evolution and it is exerted by the huntingtin N-terminal domain.