Transcriptional regulation and cellular strategies in neuroregeneration

Abstract

Neurogenesis and gliogenesis are processes that occur during development of the CNS as well as after insult of the nervous system. These tightly regulated processes take place in specialized niches during embryogenesis and adulthood to generate functional cells, starting from defined progenitor cells such as neural stem cells (NSCs). Here we took a multifaceted experimental approach to better understand NSC biology both in vitro and in vivo. Transcriptional regulation is essential since the expression of specific genes is the key to control timing and fate of the differentiation process. In this thesis two NSC transcriptional regulators, Foxp1 and Sox4 are shown to be crucial for control of neurogenesis and gliogenesis respectively. Mutations in the Foxp1 gene have been associated with speech defects, autism and other intellectual disabilities (Hamdan et al., 2010; Le Fevre et al., 2013; Lozano et al., 2015; Palumbo et al., 2013; Sollis et al., 2016), as well as being defined as necessary for neurogenesis (Bacon et al., 2015). In the work presented in this thesis, we sought to define the molecular mechanisms mediated by Foxp1 that regulate NSC differentiation. Sox4 has been described as inhibitor of gliogenesis and myelination in oligodendrocyte precursor cells (Bartesaghi et al., 2015; Hoser et al., 2007; Potzner et al., 2007). In this context we investigated the role and molecular mechanisms underlying Sox4-mediated regulation of oligodendrogenesis. The use of cellular strategies to repair CNS insults has been widely investigated in recent years (Daadi et al., 2010; Donega et al., 2013; Park et al., 2002; Titomanlio et al., 2011; van Velthoven et al., 2010c). Here we further evaluate the therapeutic potential of NSCs and MSCs to treat perinatal hypoxicischemic brain damage (HI). Moreover, the hypothesis of the use of exosomes as a cell-free alternative as a therapeutic option upon brain insults and HI is here examined.