Mitotic spindle orientation is essential for cell fate decisions, epithelial maintenance, and tissue morphogenesis. further give an overview on instructive external signals that control spindle orientation in tissues. Finally, we discuss the influence of cell geometry and mechanical forces on spindle orientation. grip\motif\polypeptide 75DlgDiscs largeDsh DEP domaindishevelled/EGL10/pleckstrin domainEB1end binding family member 1EB3end binding family member 3ECMextracellular matrixEdechinoidERMEzrinCradixinCmoesinEVLenveloping cell layer4.1Gband 4.1\like 2 protein/EPB41L24.1Rband 4.1 protein/EPB41FzCDshfrizzled/disheveledGAPGTPase\activating proteinGEFguanine exchange factorGOA1guanine AG-1024 (Tyrphostin) nucleotide\binding protein G (o) subunit alphaGPA16G protein alpha subunitGPRG protein regulatorGPR1/2G protein regulator 1/2HTThuntingtinILKintegrin\linked kinaseInscinscuteableLgl neuroblasts thus AG-1024 (Tyrphostin) allowing asymmetric cell divisions 3. Similarly, during the first division of the zygote, spindle displacement toward the posterior pole is crucial for the production of two daughter cells of asymmetric size and different fate 4, 5. Third, daughter cells resulting from a division must be correctly positioned in order to maintain tissue structure and/or contribute to tissue morphogenesis in metazoans. In epithelia, planar orientation of divisions is required for the maintenance of daughter cells in the plane of the tissue 6, 7, 8. In addition, polarized orientation of cell divisions within the epithelium plane can contribute to tissue elongation 9, 10. Conversely, spindle orientation along the apico\basal axis is necessary for asymmetric cell division and epithelial stratification during skin development in the mouse embryo 11. Altogether, spindle orientation and positioning are Rabbit Polyclonal to SLC30A4 involved in fundamental developmental processes and in tissue homeostasis, and their deregulation has been correlated with different pathologies, including microcephaly and cancer 12, 13. This underscores the importance of understanding the mechanisms mediating these processes. The multiple roles of oriented cell divisions in animal development and pathologies have been reviewed elsewhere 14, 15, 16, 17, 18, 19. The focus of this review was to provide a comprehensive overview of the mechanisms and regulatory inputs of spindle orientation in metazoans. Of note, spindle positioning mechanisms are also extensively studied during asymmetric division of the budding yeast; however, this model shows important differences to higher eukaryotes and therefore will not be discussed here (see Box?1 for a brief overview). Box?1:?Spindle orientation in budding yeast Spindle positioning is well characterized during the asymmetric division of the budding yeast and models of asymmetric cell division prompted a series of studies that linked regulators of cell polarity with the molecular control of spindle positioning and orientation. In this context, a role of Gi subunits of heterotrimeric G proteins and the adaptor molecule LGN (leucineCglycineCasparagine) in spindle orientation was initially identified in embryonic neuroblasts 21, 22. Later work revealed the evolutionary conservation of this complex in numerous metazoans, and how it interacts with the NuMA (nuclear and mitotic apparatus) adaptor to recruit the dynein motor complex to the cell cortex in symmetrically and asymmetrically dividing cells. Indeed, in most animal cell types oriented cell divisions involve the transmission of localized pulling forces located at the cell cortex to astral microtubules, resulting in the positioning of the mitotic spindle. As a consequence, the cell cortex, the specific mechanisms that recruit and localize force generators, and the astral microtubule network have emerged as the three essential levels of regulation for spindle orientation. In this review, we will first briefly review the role of the so\called LGN complex and discuss recent literature that refines our understanding of the spatial and temporal regulation of the activity of this complex. We will also discuss recently described alternative mechanisms for the recruitment of force generators at the cell cortex. In the second part of the review, we will AG-1024 (Tyrphostin) review the emerging roles of the actin cortex on spindle orientation. In the third part, we will show how mechanisms that regulate astral microtubule nucleation, dynamics,.