Regulation of mitotic spindle orientation: an integrated view

Abstract

Mitotic spindle orientation is essential for cell fate decisions, epithelial maintenance, and tissue morphogenesis. In most animal cell types, the dynein motor complex is anchored at the cell cortex and exerts pulling forces on astral microtubules to position the spindle. Early studies identified the evolutionarily conserved Gai/ LGN/NuMA complex as a key regulator that polarizes cortical force generators. In recent years, a combination of genetics, biochemistry, modeling, and live imaging has contributed to decipher the mechanisms of spindle orientation. Here, we highlight the dynamic nature of the assembly of this complex and discuss the molecular regulation of its localization. Remarkably, a number of LGNindependent mechanisms were described recently, whereas NuMA remains central in most pathways involved in recruiting force generators at the cell cortex. We also describe the emerging role of the actin cortex in spindle orientation and discuss how dynamic astral microtubule formation is involved. We 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.

Spindle orientation: a question of complex positioning

“…This is consistent with earlier studies showing that cortical actin is required for the pulling force in epithelial cells (Busson et al, 1998;Kaushik et al, 2003;Machicoane et al, 2014;Nakajima et al, 2013). Additional roles for actin in spindle orientation have also recently been proposed (as reviewed by di Pietro et al, 2016).…”

“…Together, these proteins are believed to secure a complex consisting of dynein/dynactin motor at the cell cortex, and thus localise the astral-microtubule pulling force. A model that describes their interaction is well established in the literature (reviewed by di Pietro et al, 2016). Briefly, Gαi, which attaches to the plasma membrane, anchors Pins/LGN by binding to its C-terminus (Du and Macara, 2004;Gotta and Ahringer, 2001;Kaushik et al, 2003;Nipper et al, 2007;Schaefer et al, 2000;Yu et al, 2003).…”

Cell biological mechanisms regulating chick neurogenesis

“…(Morin et al, 2007, Peyre et al, 2011, Saade et al, 2013, Spear and Erickson, 2012, Wilcock et al, 2007 including regulation of mitotic spindle orientation (see (di Pietro et al, 2016)). In this short review, we discuss recent studies that advance our understanding of cell biological mechanisms which underpin the activities of key signalling pathways that regulate neurogenic cell fate, and that orchestrate neuronal delamination.…”

Physical Limits on the Precision of Mitotic Spindle Positioning by Microtubule Pushing forces

“…For example, directed cell movements lead to stratification [18] or elongation of tissues along a specified axis [19] ; long-range forces induce cell flow within developing epithelia [20] ; and intracellular forces position and orient the mitotic spindle to specify the plane of cell division. The orientation of the plane of cell division in turn determines the location of the daughter cells within the tissue leading to polarized growth [21,22] , and, often, differences in cell fate [23] . Thus, mechanical processes can complement chemical gradients by altering tissue organization.…”