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Digital archive of theses discussed at the University of Pisa


Thesis etd-07282022-135226

Thesis type
Tesi di dottorato di ricerca
Thesis title
Microcephaly-causing viruses disrupt pTBK1 and FOXG1 activity in human neural stem cells and their progeny
Academic discipline
Course of study
tutor Prof. Onorati, Marco
  • Chikungunya virus
  • Coxsackie B virus
  • Cytomegalovirus
  • FGF2
  • FOXG1
  • Herpes simplex virus 2
  • human
  • microcephaly
  • neural stem cells
  • neurons
  • TBK1
  • Zika virus
Graduation session start date
Release date
Zika virus (ZIKV) outbreak posed an urgent need to unravel the molecular mechanisms involved of microcephaly induced by neurotropic pathogens of the TORCH group. Here, I aim to investigate the events during TORCH viral infection, using innovative human neural progenitor cells (NPCs) derived from both human fetal neocortex tissue (neuroepithelial stem [NES] cells) and induced pluripotent stem cells (hiPS-NPCs). I focused on two main targets affecting cell cycle progression of NPCs. pTBK1, a kinase involved in the antiviral innate immune response, results delocalized from centrosomes to mitochondria following ZIKV molecular. To verify whether the same mechanism could be involved in other viral infections, I selected four viruses: three TORCH members (Herpes simplex virus, Cytomegalovirus, and Coxsackie B virus) and Chikungunya virus, which is not a TORCH member but it is known to employ the same primary vector of ZIKV and can induce encephalitis and developmental delay. I found that an event at the base of microcephaly etiogenesis is shared by different TORCH and non-TORCH viruses in NES cells and NES cell-derived neurons. Then, I focused on another player involved in NPC proliferation and self-renewal, FOXG1 gene, coding for a forebrain transcription factor and mutations of which are also associated with severe developmental disorders, including microcephaly. Specifically, I investigated ZIKV impact on FOXG1 protein. I found the nuclear displacement and reduction of FOXG1 following infection in hiPS-NPCs. Collectively, our data suggest new potential targets of congenital microcephaly.