The kinases PIG-1 and PAR-1 act in redundant pathways to regulate asymmetric division in the EMS blastomere of C. elegans

Abstract

The PAR-1 kinase of C. elegans is localized to the posterior of the one-cell embryo and its mutations affect asymmetric spindle placement and partitioning of cytoplasmic components in the first cell cycle. However, par-1 mutations do not cause failure to restrict the anterior PAR polarity complex to the same extent as mutations in the posteriorly localized PAR-2 protein. Further, it has been difficult to examine the role of PAR-1 in subsequent divisions due to the early defects in par-1 mutant embryos. Here we show that the PIG-1 kinase acts redundantly with PAR-1 to restrict the anterior PAR-3 protein for normal polarity in the one-cell embryo. By using a temperature sensitive allele of par-1, that exhibits enhanced lethality when combined with a pig-1 mutation, we have further explored roles for these genes in subsequent divisions. We find that both PIG-1 and PAR-1 regulate spindle orientation in the EMS blastomere of the four-cell stage embryo to ensure that it undergoes an asymmetric division. In this cell, PIG-1 and PAR-1 act in parallel pathways for spindle positioning, PIG-1 in the MES-1/SRC-1 pathway and PAR-1 in the Wnt pathway.

PIG-1 MELK-dependent phosphorylation of nonmuscle myosin II promotes apoptosis through CES-1 Snail partitioning

“…In pig-1 mutants, the HSN/PHB neuroblast divides symmetrically to give rise to two cells of similar sizes, both of which survive and can divide to give rise to a total of two HSNs and two PHBs [14]. Subsequent analyses in early C. elegans embryos confirmed a role for pig-1 in asymmetric cell division and demonstrated that this function is not specific to cell divisions that give rise to an apoptotic death [16][17][18]. Furthermore, in this context, pig-1 was found to act in a pathway that is redundant with a pathway that is dependent on the gene par-1, which encodes a serine/threonine kinase similar to PIG-1 [16].…”

“…Subsequent analyses in early C. elegans embryos confirmed a role for pig-1 in asymmetric cell division and demonstrated that this function is not specific to cell divisions that give rise to an apoptotic death [16][17][18]. Furthermore, in this context, pig-1 was found to act in a pathway that is redundant with a pathway that is dependent on the gene par-1, which encodes a serine/threonine kinase similar to PIG-1 [16]. Several observations suggest that pig-1 acts in asymmetric cell division by controlling the distribution of nonmuscle myosin II NMY-2 in dividing cells [18,19].…”

PIG-1 MELK-dependent phosphorylation of nonmuscle myosin II promotes apoptosis through CES-1 Snail partitioning

“…We present evidence in support of the notion that pig-1 MELK controls daughter cell size asymmetry and CES-1 Snail gradient formation in the NSM neuroblast lineage by causing the phosphorylation at S211 and S1974 of nonmuscle myosin II NMY-2 ( Figure 7A). PIG-1 is structurally and functionally similar to the C. elegans kinase PAR-1 (Liro et al, 2018), which has been shown to physically interact with NMY-2 (Guo and Kemphues, 1996). Therefore, we consider it likely that PIG-1 directly interacts with and phosphorylates NMY-2.…”

“…In pig-1 mutants, the HSN/PHB neuroblast divides symmetrically to give rise to two cells of similar sizes, both of which survive and can divide to give rise to a total of two HSNs and two PHBs (Cordes et al, 2006). Subsequent analyses in early C. elegans embryos confirmed a role for pig-1 in asymmetric cell division and demonstrated that this function is not specific to cell divisions that give rise to an apoptotic death (Liro et al, 2018;Morton et al, 2012;Pacquelet et al, 2015). Furthermore, in this context, pig-1 was found to act in a pathway that is redundant with a pathway that is dependent on the gene par-1, which encodes a serine/threonine kinase similar to PIG-1 (Liro et al, 2018).…”

“…Subsequent analyses in early C. elegans embryos confirmed a role for pig-1 in asymmetric cell division and demonstrated that this function is not specific to cell divisions that give rise to an apoptotic death (Liro et al, 2018;Morton et al, 2012;Pacquelet et al, 2015). Furthermore, in this context, pig-1 was found to act in a pathway that is redundant with a pathway that is dependent on the gene par-1, which encodes a serine/threonine kinase similar to PIG-1 (Liro et al, 2018). Several observations suggest that pig-1 acts in asymmetric cell division by controlling the distribution of nonmuscle myosin II NMY-2 in dividing cells (Ou et al, 2010;Pacquelet et al, 2015).…”