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    • Studying the regulatory role of FGF signaling in mammalian

    2018-10-24

    Studying the regulatory role of FGF signaling in mammalian neural development primarily focuses upon the VZ of the neocortex (after neural tube formation, discussed above), whereas its earlier role in neural induction is less explored. This may be due to the inaccessibility of embryonic tissues at the stage of neural plate formation (~E7.5-E8.7).Therefore, the function of FGF signaling in neural induction in vivo are primarily derived from the studies of Xenopus (Sater et al., 2003; Kuroda et al., 2005) and chickens (Streit et al., 2000; Wilson et al., 2000; Stern, 2006; Stavridis et al., 2007), which found the FGF signaling played a pivotal role in neural induction. Our in-vitro developmental modeling system provided an invaluable tool to explore early neural development in human. We found that FGF2 and its receptors are expressed at around neural plate formation and a constant blockade of the FGF2/p-ERK pathway with PD184352 treatment abolished neural induction and adopted non-neural fate, which is in line with others\' and our previous findings in mouse and human ESCs (Kunath et al., 2007; Stavridis et al., 2007; Cohen et al., 2010; Lin et al., 2010; Matulka et al., 2013). Interestingly, a constant blockade or augmentation of FGF2 signaling (other than the FGF2/p-ERK pathway, e.g. PI3 and AKT/PKB pathways) during neural induction significantly disrupted neural rosette formation, but did not prevent 2-deoxy-d-glucose from undergoing neural induction, which resulted in impeding or retarding in neurogenesis. In contrast to the proliferating effect of FGF2 on NSCs, our results showed that exogenous FGF2 impaired neural rosette formation. This might be attributed to excess FGF2 derailing the polarization of ZO-1 during rosette structuring, and this led to abolition of the apical-basal FGF2 signaling gradient by disrupting FGFR1 apical localization. Our results suggest that the FGF2 signaling gradient in neural rosettes is crucial in the NSC niche to expand NSCs and to execute an orderly neural differentiation by diversifying its regulatory roles with various FGF signaling pathways. We further established the impairment in neurogenesis mediated by the dysregulation of FGF2 signaling may be attributed to the disarrangement of ZO-1, a marker of polarity, in the apical location, which resulted in the deformation of neural rosettes that might lead to disarray of the NSC niche within rosettes and causes abnormalities in neurogenesis. This hypothesis was corroborated with our findings that knocking down ZO-1 caused disorganized neural rosettes, dislodging apical locations of FGF2 and FGFR1, and a delay in neurogenesis, the phenotypes of which were similar to those observed in FGF2 signaling inhibition, suggesting reciprocal actions between NSC niches and polarized elements in neural rosettes to maintain proliferating environment for orderly neurogenesis. This notion was concomitant with our observation that NSCs dissociated from neural rosettes exhibited a propensity to undergo an asymmetric division.Our results echoed the findings that proteins involved in polarity play essential roles in neurogenesis (Compagnucci et al., 2015; Banda et al., 2015; Singh and Solecki, 2015).
    Conclusion The following are the supplementary data related to this article.
    Acknowledgements
    Introduction Adipose tissue is a versatile organ not limited to the lipidic function, but also exerting significant endocrine and inflammatory activity and influencing vascular function (Meissburger et al., 2016; Chudek and Wiecek, 2006). From a physiological standpoint, the development of adipose tissue within the body is not univocal and many factors cooperate to orchestrate its varied distribution, including genetic background and variations due to clinical conditions (Gesta et al., 2007). Furthermore, the adipose tissue is highly heterogeneous and recent clinical evidence indicates that both the compartmentalization and anatomical deposition of fat depots considerably differ in metabolic and physiological profiles (Kwok et al., 2016; Lee et al., 2013). These dissimilarities have been ascribable to a different developmental origin and epigenetic regulation, implying profound differences in depot-specific patterning genes and pathway activity mainly related to the anatomic region of origin (Gesta et al., 2006; Pinnick et al., 2014; Collas, 2010; Karantalis and Hare, 2015). Notably, differences in adipose depots also cause clinical consequences in those pathologies where fat tissue exerts a pathophysiological role such as endocrinological, metabolic and cardiac disorders, obesity, diabetes and cancer (Lapidus et al., 1984; Despres, 2006; Lim and Meigs, 2013). For instance, a clear association between cardiovascular risk and type of fat depot has been clearly elucidated. Visceral rather than subcutaneous adipose tissue has been suggested to be directly proportional to adverse cardiac and cancer risk due to the prevalence of oxidative and inflammatory systemic states (Pou et al., 2007; Misra et al., 1997; Harada et al., 2015; Chau et al., 2014).