Mitotic spindle (DIS)orientation and DISease: cause or consequence?

Abstract

Correct alignment of the mitotic spindle during cell division is crucial for cell fate determination, tissue organization, and development. Mutations causing brain diseases and cancer in humans and mice have been associated with spindle orientation defects. These defects are thought to lead to an imbalance between symmetric and asymmetric divisions, causing reduced or excessive cell proliferation. However, most of these disease-linked genes encode proteins that carry out multiple cellular functions. Here, we discuss whether spindle orientation defects are the direct cause for these diseases, or just a correlative side effect.

Figure 1.

Orientation of the mitotic spindle: symmetric vs. asymmetric divisions. In polarized cells, orientation of the spindle perpendicular to the polarity axis causes a symmetric (proliferative) division (A). However, spindle orientation parallel to the polarity axis results in an asymmetric (differentiative) division (B).

Figure 2.

Spindle orientation is regulated by a conserved set of molecules in metazoans. (A) The C. elegans one-cell embryo is polarized along the anterior–posterior axis and divides asymmetrically in a somatic anterior cell (AB) and a posterior germline precursor cell (P1). The conserved PAR (partitioning defective) proteins are localized asymmetrically at the cortex: PAR-3, PAR-6, and PKC-3 at the anterior and PAR-1 and PAR-2 at the posterior. Spindle positioning is regulated downstream of polarity by GOA-1 and GPA-16 (Gα subunits of heterotrimeric G proteins), which localize around the entire cortex (not depicted), GPR-1 and GPR-2 (receptor-independent activators of G protein signaling), LIN-5 (coil-coiled protein), and the motor dynein (not depicted; Morin and Bellaïche, 2011). GPR-1/2 and LIN-5 are enriched at the posterior cortex in a PAR-dependent manner. The data suggest a model in which the GPR–GαGDP–LIN-5 complex promotes higher activity of dynein at the posterior cortex, resulting in posterior spindle pulling (Morin and Bellaïche, 2011). (B) D. melanogaster neuroblasts are stem cell–like precursors that generate the fly’s central nervous system. They divide asymmetrically along the apical–basal axis to give rise to a self-renewed neuroblast and a ganglion mother cell. Baz (PAR-3), Par6 (PAR-6), and aPKC (PKC-3) form a complex that localizes at the apical cortex. PINS (GPR-1/2) binds to Gα and localizes to the apical complex by interacting with the Baz-binding protein Inscuteable. (C) The same set of proteins regulates spindle orientation in mammalian cells (Lechler and Fuchs, 2005; Williams et al., 2011; see also Table 1).

Figure 3.

Mammalian neuronal progenitors and spindle orientation. (A) Cell subtypes in the developing mammalian brain. NESCs, neuroepithelial stem cells. RG, radial glia. IP, intermediate progenitor. oRG, outer radial glia. IP′, transit amplifying intermediate progenitors. Adherens junctions are in red. (B) A putative role of spindle orientation in the decision of symmetric vs. asymmetric division.

Figure 4.

Equilibrium between symmetric and asymmetric divisions confers proper development and tissue homeostasis. Schematic representation of the balance between symmetric and asymmetric cell division and its relevance. ACD, asymmetric cell division. SCD, symmetric cell division.