• micrencephaly
• modelling
• neural stem cells
• neurodevelopment
• neurodevelopmental disorders
• TORCH pathogens

There are multiple questions about neurogenesis and several hypotheses try to explain how the complexity
of human brain is generated during development, anatomically and functionally speaking. The concept of
neural stem cells is intrinsically linked to neurogenesis. Neural stem cells are multipotent stem cells which
are able to self-renew and to produce a ‘tripotent’ progeny which, in turns, terminally differentiates into the
three main lineages of the central nervous system (CNS): neurons, astrocytes and oligodendrocytes. Neural
stem cells appear in a temporally and spatially orchestrated pattern during mammalian embryogenesis and
the earliest neural progenitor type to form is represented by neuroepithelial stem (NES) cells.
NES cells retain specific properties and several mechanisms regulate their type of division (symmetric Vs
asymmetric) determining the fate of a cell during neurogenesis, and, therefore, the final brain size and
architecture. During the early phase, if right symmetric divisions of NES cells do not occur, the consequence
is a depletion in the pool of stem cells with the generation of microcephaly. Microcephaly is a
neurodevelopmental disorder due to genetic mutations or environmental stresses characterized by a brain
with a significant small volume. The greatest reduction in size is shown by the cerebral cortex.
The mammalian CNS is one of the most complex anatomical structure to develop in an extended time, and it
is therefore susceptible to diverse environmental insults together with genetic ones. In fact, microcephaly
can be caused by infections of different agents during pregnancy too, like the classical group of teratogenic
pathogens “TORCH” (Toxoplasma gondii, Others, Rubella virus, Cytomegalovirus and Herpes Symplex virus).
The TORCH syndrome pathogens result in up to half of all perinatal deaths around the world, many associated
with brain malformations including microcephaly.
Nowadays, a new virus has been demonstrated to be responsible for fetal microcephaly and other severe
neurodevelopmental abnormalities, the mosquito-born flavivirus Zika virus (ZIKV). A previous work
demonstrated that human neocortical NES cells represent a unique in vitro model system to study ZIKVinduced
microcephaly. Infected NES cells were mitotically impaired with a reduction of proliferating cells,
increased apoptosis and showed a ZIKV-mediated relocation of phospho-TANK-binding kinase 1 (pTBK1), a
cellular serine-threonine kinase which plays a central role in innate antiviral immune signaling, mitosis,
microtubule dynamics as well as other important processes.
The main aim of this project is to model TORCH pathogen-induced micrencephaly with human NES cells and
to define a possible common molecular pathway by which ZIKV and other TORCH viruses induce this
pathological condition.
An important concept arises from the previous results which lay the groundwork for my research project:
pTBK1 relocation can be a cell defense mechanism upon infection of diverse viruses, not only ZIKV, resulting
in altered mitosis and cell death. In order to dissect the effects of neuroteratogenic virus infection on human
NES cells it is important to define the following aspects:
- if selected TORCH viruses (cytomegalovirus, herpes-virus-2, etc.) are able to infect human NES cells
and/or mature neurons in culture;
- If virus-infected NES cells show impaired survival and cell proliferation;
- pTBK1 relocation in mitochondria as a key TORCH pathogen strategy in order to trigger cell death
and induce brain abnormalities.