Asymmetric divisions, aggresomes and apoptosis

Abstract

Asymmetric cell division (ACD) is a fundamental process used to generate cell diversity during metazoan development that occurs when a cell divides to generate daughter cells adopting distinct fates. Stem cell divisions, for example, are a type of ACD and provide a source of new cells during development and in adult animals. Some ACDs produce a daughter cell that dies. In many cases, the reason why a cell divides to generate a dying daughter remains elusive. It was shown recently that denatured proteins are segregated asymmetrically during cell division. Here, we review data that provide interesting insights into how apoptosis is regulated during ACD and speculate on potential connections between ACD-induced cell death and partitioning of denatured proteins.

Figure 1

A comparison of a cell's “shelf-life,” PCM inheritance, aggresome inheritance and apoptotic fate during asymmetric divisions. Daughter cells from each ACD are aligned vertically as “shorter-” and “longer-” lived cells. The lowermost panel defines the cartoon depictions. (A) Fly neuroblasts are shorter lived, compared to GMC derivatives. Embryonic neuroblasts inherit aggresomes, and larval neuroblasts inherit the mother centrosome/PCM(Rebollo et al., 2007; Rujano et al., 2006; Rusan and Peifer, 2007). (B) Aggresomes associate with the PCM, and in cultured cells, segregate to the daughter with a higher apoptotic fate potential(Rujano et al., 2006). (C) Aggresomes are prevalent in the shorter-lived differentiated cells of the human intestinal crypt(Rujano et al., 2006).(D) NSM neuroblast divisions generate an apoptotic daughter. The inheritance pattern of the mother centrosome/PCM and aggresomes are unknown.

Figure 2

Model for the division of the NSM neuroblast. In the wild-type lineage (top), the gene ces-1 is inhibited by CES-2 and DNJ-11. How DNJ-11 inhibits ces-1 is unclear. CES-1 protein is asymmetrically distributed to the NSM, where it inhibits binding of the HLH-2/HLH-3 heterodimer to sequences that regulate the proapoptotic gene egl-1, preventing expression expression of egl-1. Lack of CES-1 protein in the NSM sister allows HLH-2/HLH-3 to promote egl-1 expression, which leads to apoptosis. (Bottom) A gain-of-function mutation in ces-1 or loss-of-function mutations in either ces-2 or dnj-11 lead to excess expression of ces-1, causing the daughter cells to become more equivalent in size and the NSM sister to survive. Adapted from Hatzold and Conradt(Hatzold and Conradt, 2008).