Timing cell-fate determination during asymmetric cell divisions

Abstract

From invertebrates to mammals, cell-cycle progression during an asymmetric cell division is accompanied by precisely timed redistribution of cell-fate determinants so that they segregate asymmetrically to enable the two daughter cells to choose different fates. Interestingly, studies on how cell fates are specified in such divisions reveal that the same fate determinants can be reiteratively used to specify a variety of cell types through multiple rounds of cell divisions or to exert seemingly contradictory effects on cell proliferation and differentiation. Here I summarize the molecular mechanisms governing asymmetric cell division and review recent findings pointing to a novel mechanism for coupling intracellular signaling and cell-cycle progression. This mechanism uses changes in the morphology, subcellular distribution, and molecular composition of cellular organelles like the Golgi apparatus and centrosomes, which not only accompany the progression of cell cycle to activate but also temporally constrain the activity of fate determinants during asymmetric cell divisions.

Figure 1

Reiterative use and diverse roles of the cell-fate determinant Numb during asymmetric cell divisions. (a) Drosophila SOP cells. (b) Drosophila neuroblasts. (c) Mammalian radial glial cells. G, glial cell; H, hair cell; N, neuron; S, socket cell; Sh, sheath cell.

Figure 2

A Model for differentially regulating Numb signaling during mammalian neurogenesis through Golgi fragmentation and reconstitution. (a) The subcellular distribution of the exogenous, GFP-tagged mouse Numb protein (in green) and the endogenous ACBD3 (in red) in interphase NIE115 cells, a mouse neuroblastoma cell line. (b) Numb proteins promote self-renewal when neural stem (progenitor) cells divide asymmetrically to self-renew and produce a neuron, but this occurs only when ACBD3 (in red) is present in the cytosol after Golgi fragmentation during mitosis. Newly synthesized Numb proteins subsequently accumulate in newborn neurons but, with ACBD3 localized to the Golgi, tap into a different pathway to promote neuronal differentiation. Stem cells in many tissues may use this mechanism to balance self-renewal and differentiation.