Comparative genetic, proteomic and phosphoproteomic analysis of C. elegans embryos with a focus on ham-1/STOX and pig-1/MELK in dopaminergic neuron development

Offenburger, Sarah-Lena; Bensaddek, Dalila; Murillo, Alejandro Brenes; Gartner, Anton

doi:10.1038/s41598-017-04375-4

Cited by 13 publications

(10 citation statements)

References 63 publications

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“…The pig-1 single and pig-1 ham-1 double mutants, however, produce similar Q.a DCSA phenotypes ( Fig S2). The same epistatic interactions between ham-1 and pig-1 were previously observed for other lineages [8,18].…”

Section: Pig-1 Does Not Mediate the Regulation Of Qa Dcsa By Ham-1supporting

confidence: 82%

The Caenorhabditis elegans HAM-1 protein modifies G protein signaling and membrane extension to reverse the polarity of asymmetric cell division

Teulière

Garriga

2018

Preprint

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Asymmetric divisions often produce daughter cells that differ in both fate and size. The Caenorhabditis elegans HAM-1 protein regulates both daughter cell fate and daughter cell size asymmetry (DCSA) in a subset of asymmetric divisions. Here we focus on the divisions of the Q.a and Q.p neuroblasts, which use distinct mechanisms to divide with opposite polarity. Q.a divides by a ham-1-dependent, spindle-independent, myosindependent mechanism to produce a smaller anterior daughter that dies, whereas Q.p divides by a ham-1-independent, spindle-dependent, myosin-independent mechanism to produce a smaller posterior daughter that dies. Despite these differences, we found that membrane extension at the posterior of Q.a and at the anterior of Q.p promoted DCSA in these cells by a Wiscott-Aldrich protein (WASp)-dependent mechanism and that in ham-1 mutant Q.a divisions, the polarity of this extension was reversed. In addition, the spindle moved posteriorly during the Q.a division in a ham-1 mutant, a phenotype normally exhibited by Q.p. We found that this spindle movement in wild-type Q.p divisions required Ga proteins that promote spindle movement in other asymmetric divisions, and GPR-1, a protein involved in linking G proteins to microtubule asters, localized to the posterior cortex of Q.p. Genetic interactions suggest that ham-1 mutant Q.a divisions also require Ga proteins function to divide with a reversed polarity. The transformation of Q.a to Q.p-like polarity in the ham-1 mutant, however, appeared incomplete: ham-1 loss did not alter the asymmetric localization of the non-muscle myosin NMY-2 to the anterior cortex of Q.a. A GFP tagged ham-1 transgene revealed that Q.a but not Q.p expressed ham-1. Finally, we show that HAM-1 has both cortical and nuclear functions in Q,a DCSA. We propose a model where HAM-1 modifies a default Q.p-type polarity by localizing WASp function to the posterior Q.a membrane and by interfering with G-protein mediated spindle movement. Author SummaryOne way that animals produce different cell types is by asymmetric cell division, where a cell divides to produce daughter cells that differ in fate. Much is known about the mechanisms that polarize dividing cells to generate daughters that differ in fate. Some asymmetric cell divisions also result in daughters that differ in size, and the mechanisms that regulate how cells generate an asymmetric cleavage plane are poorly understood.In neural progenitors of the nematode Caenorhabditis elegans, two distinct mechanisms generate daughter cells of different size. One type requires movement of the mitotic spindle, which then defines the plane of the cell division. The other is spindleindependent. Here, we study two cells that divide with opposite polarities using these two mechanisms. We find that in the absence of the protein HAM-1, which has been reported to regulate gene transcription, the cell that normally divides using a spindleindependent mechanism now divides with a reversed polarity using a spindle-dependent mechanism. Our findings suggest ...

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Section: Pig-1 Does Not Mediate the Regulation Of Qa Dcsa By Ham-1supporting

confidence: 82%

The Caenorhabditis elegans HAM-1 protein modifies G protein signaling and membrane extension to reverse the polarity of asymmetric cell division

Teulière

Garriga

2018

Preprint

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“…elegans nonmuscle myosin II NMY-2 has been proposed to be a target of PIG-1 MELK [ 19 , 40 ]. Furthermore, NMY-2 phosphorylation at two specific residues, serine 211 (S211) and serine 1974 (S1974), was found to be reduced in pig-1 mutants [ 41 ]. Using a nmy-2 CRISPR knock-in allele that produces a functional NMY-2::GFP fusion protein ( nmy-2 ( cp13 ), nmy-2 :: gfp + LoxP ) [ 42 ], we visualized NMY-2 in the NSMnb.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2020

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The mechanism(s) through which mammalian kinase MELK promotes tumorigenesis is not understood. We find that the C. elegans orthologue of MELK, PIG-1, promotes apoptosis by partitioning an anti-apoptotic factor. The C. elegans NSM neuroblast divides to produce a larger cell that differentiates into a neuron and a smaller cell that dies. We find that in this context, PIG-1 MELK is required for partitioning of CES-1 Snail, a transcriptional repressor of the pro-apoptotic gene egl-1 BH3-only. pig-1 MELK is controlled by both a ces-1 Snail-and par-4 LKB1-dependent pathway, and may act through phosphorylation and cortical enrichment of nonmuscle myosin II prior to neuroblast division. We propose that pig-1 MELK-induced local contractility of the actomyosin network plays a conserved role in the acquisition of the apoptotic fate. Our work also uncovers an auto-regulatory loop through which ces-1 Snail controls its own activity through the formation of a gradient of CES-1 Snail protein.

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“…Further analysis of these studies revealed that most extra cells arise appear to arise from 21 of 34 (32 embryonic and 2 post-embryonic) neuroblast divisions that produce an anterior cell fated to die and a posterior cell that survives and adopts either a neuronal or mitotic fate [ 1 , 2 ] ( Table 1 )( Fig 1 ). The ham-1 mutant HSN/PHB, ALN/PLM and CEPD/URX lineages are also missing neurons, resulting from either ectopic apoptosis or a failure of the neurons to differentiate and to express the appropriate marker [ 7 , 14 , 15 , 28 , 29 ].…”

Section: Resultsmentioning

confidence: 99%

The Caenorhabditis elegans gene ham-1 regulates daughter cell size asymmetry primarily in divisions that produce a small anterior daughter cell

et al. 2018

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C. elegans cell divisions that produce an apoptotic daughter cell exhibit Daughter Cell Size Asymmetry (DCSA), producing a larger surviving daughter cell and a smaller daughter cell fated to die. Genetic screens for mutants with defects in apoptosis identified several genes that are also required for the ability of these divisions to produce daughter cells that differ in size. One of these genes, ham-1, encodes a putative transcription factor that regulates a subset of the asymmetric cell divisions that produce an apoptotic daughter cell. In a survey of C. elegans divisions, we found that ham-1 mutations affect primarily anterior/posterior divisions that produce a small anterior daughter cell. The affected divisions include those that generate an apoptotic cell as well as those that generate two surviving cells. Our findings suggest that HAM-1 primarily promotes DCSA in a certain class of asymmetric divisions.

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Comparative genetic, proteomic and phosphoproteomic analysis of C. elegans embryos with a focus on ham-1/STOX and pig-1/MELK in dopaminergic neuron development

Cited by 13 publications

References 63 publications

The Caenorhabditis elegans HAM-1 protein modifies G protein signaling and membrane extension to reverse the polarity of asymmetric cell division

The Caenorhabditis elegans HAM-1 protein modifies G protein signaling and membrane extension to reverse the polarity of asymmetric cell division

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

The Caenorhabditis elegans gene ham-1 regulates daughter cell size asymmetry primarily in divisions that produce a small anterior daughter cell

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