HTT forms a complex with

HTT forms a complex with dynein and dynactin in neurons to promote axonal microtubule-based vesicular transport (Caviston et al., 2007; Gauthier et al., 2004). Here, we demonstrate that HTT regulates spindle orientation through its interaction with dynein. Dynein and dynactin are recruited to the cell cortex by the Gαi/Gαo-LGN-NUMA complex where they generate pulling forces that control spindle position and orientation (Kiyomitsu and Cheeseman, 2012; Kotak et al., 2012; Woodard et al., 2010). During metaphase, a signal comprising the spindle pole-localized polo-like kinase 1 (PLK1) regulates dynein localization by controlling the interaction between dynein/dynactin and its upstream cortical targeting factors NUMA and LGN (Kiyomitsu and Cheeseman, 2012). Dynein-dynactin movement to the astral microtubule plus ends involves CLIP-170 and LIS1 (Coquelle et al., 2002; Faulkner et al., 2000). In Drosophila neuroblasts, dynein and the plus-end motor KHC73/KIF13B act in synergy at microtubule plus ends to promote PINS-mediated spindle positioning (Lu and Prehoda, 2013). However, the microtubule-associated motors mediating dynein-dynactin transport to the astral microtubule plus ends are still unknown. We propose that LGN, NUMA, dynein, and dynactin are recruited to the cell cortex through an astral microtubule- and kinesin 1-dependent transport that is regulated by HTT. How this mechanism is coordinated in space and time with the other pathways remains to be determined. Finally, the regulation of asymmetric/symmetric divisions is essential for the maintenance of stem cell populations, and it may also be key during tumorigenesis (Cicalese et al., 2009; Driessens et al., 2012; Quyn et al., 2010). In mammary tumoral tissues, symmetric divisions of cancer stem FH535 may contribute to tumor growth (Cicalese et al., 2009). Thus, our results not only open new lines of investigation for unraveling the mechanisms controlling stem cell self-renewal and cell fate specification in the mammary gland but may also have broader implications for the role of cell divisions in cancer biology.
Experimental Procedures
Acknowledgments
Introduction Adult neurogenesis is a distinctive feature of the telencephalon in the mammalian brain. Neurogenesis proceeds by neural stem cells (NSCs), giving rise to transit-amplifying cells, which subsequently differentiate into neuroblasts and mature neurons (Bonaguidi et al., 2012; Malatesta et al., 2000; Noctor et al., 2001; Seri et al., 2004). Despite the presence of NSCs and the apparent constitutive neurogenesis in the subventricular zone of the lateral ventricles and in the hippocampus, the ability of mammals to replace neurons that are lost due to injury or during the course of progressive neurodegenerative diseases are modest at best (Arias-Carrión et al., 2007, 2009; Kernie and Parent, 2010). In contrast to mammals, several nonmammalian vertebrate species, such as teleost fishes and salamanders, display a remarkable ability to regenerate brain tissue by processes that involve extensive neurogenic events (for a recent review, see Grandel and Brand, 2013). Studies over the past years have substantially increased our understanding of adult neurogenesis in these species (e.g., Chapouton et al., 2007). Both nongenetic and genetic cell-tracking studies revealed that cells with radial glia features act as neuronal progenitors in fishes and salamanders. These cells line the ventricular system, express GFAP, and have long processes reaching to the pial surface (Berg et al., 2010; Kroehne et al., 2011; Maden et al., 2013; Pérez-Cañellas and García-Verdugo, 1996). The zebrafish telencephalon has been shown to have a distinctive heterogeneity among ventricular cells, in terms of anatomical localization and protein-expression profiles (Chapouton et al., 2010; Ganz et al., 2010; März et al., 2010). Neurogenic regions have been mapped and revealed an uneven distribution of actively dividing cells with progenitor potential along the ventricular system in anamniotes (Adolf et al., 2006; Berg et al., 2010; Kaslin et al., 2009). Some of these studies indicated that a correlation between the distribution of active neurogenic niches and regions with neuroregenerative capacity exists (Zupanc and Zupanc, 2006); however, the two are not necessarily linked to each other. For example, studies in the aquatic salamander Notophthalmus viridescens (red-spotted newt) showed extensive regeneration following ablation of neurons in regions that are essentially devoid of neurogenesis under normal conditions (Berg et al., 2010; Parish et al., 2007). Nevertheless, the newt telencephalon harbors several proliferative hot spots, such as the lateral wall of the ventricle adjacent to the dorsal pallium (Dp) and the lateral wall of the ventricle adjacent to the bed nucleus of the stria terminalis (Bst) (Berg et al., 2010). Hence, the telencephalon is an ideal model for studying the cellular composition and regulatory mechanisms of neuronal regeneration in an environment, which is permissive for constitutive neurogenesis.