The Actomyosin-Anilloseptin Contractile Ring to compression of its own membrane microdomain attachment sites, can account for numerous otherwise puzzling observations and warrants further investigation using multiple systems and methods.
Rho-dependent proteins control assembly of the cytokinetic contractile ring, yet it remains unclear how those proteins guide ring closure and how they promote subsequent formation of a stable midbody ring. Citron kinase is one important component required for midbody ring formation but its mechanisms of action and relationship with Rho are controversial. Here, we conduct a structure–function analysis of the Drosophila Citron kinase, Sticky, in Schneider’s S2 cells. We define two separable and redundant RhoGEF/Pebble-dependent inputs into Sticky recruitment to the nascent midbody ring and show that each input is subsequently required for retention at, and for the integrity of, the mature midbody ring. The first input is via an actomyosin-independent interaction between Sticky and Anillin, a key scaffold also required for midbody ring formation. The second input requires the Rho-binding domain of Sticky, whose boundaries we have defined. Collectively, these results show how midbody ring biogenesis depends on the coordinated actions of Sticky, Anillin, and Rho.
Our work identifies the genetic cause of LP in these two families, demonstrates the phenotypic range of the condition, implicates dysregulation of extracellular matrix homoeostasis genes in its pathogenesis, and highlights the link between TGF-β/SMAD signalling, growth/differentiation factor 6 and syndecan-2. We propose that LP is an additional member of the growing 'TGF-β-pathies' group of musculoskeletal disorders, which includes Myhre syndrome, acromicric dysplasia, geleophysic dysplasias, Weill-Marchesani syndromes and stiff skin syndrome. Identification of a systemic sclerosis-protective SDC2 variant lays the foundation for exploration of the role of syndecan-2 in systemic sclerosis in the future.
Summary
During cytokinesis, an actomyosin contractile ring drives the separation of the two daughter cells. A key molecule in this process is the inositol lipid PtdIns(4,5)P
2
, which recruits numerous factors to the equatorial region for contractile ring assembly. Despite the importance of PtdIns(4,5)P
2
in cytokinesis, the regulation of this lipid in cell division remains poorly understood. Here, we identify a role for IPIP27 in mediating cellular PtdIns(4,5)P
2
homeostasis. IPIP27 scaffolds the inositol phosphatase oculocerebrorenal syndrome of Lowe (OCRL) by coupling it to endocytic BAR domain proteins. Loss of IPIP27 causes accumulation of PtdIns(4,5)P
2
on aberrant endomembrane vacuoles, mislocalization of the cytokinetic machinery, and extensive cortical membrane blebbing. This phenotype is observed in
Drosophila
and human cells and can result in cytokinesis failure. We have therefore identified IPIP27 as a key modulator of cellular PtdIns(4,5)P
2
homeostasis required for normal cytokinesis. The results indicate that scaffolding of inositol phosphatase activity is critical for maintaining PtdIns(4,5)P
2
homeostasis and highlight a critical role for this process in cell division.
Rho-dependent proteins control assembly of the cytokinetic contractile ring (CR), yet it remains unclear how those proteins guide ring closure and how they promote subsequent formation of a stable midbody ring (MR). Citron kinase is one important component required for MR formation but its mechanisms of action and relationship with Rho are controversial.Here, we conduct a structure-function analysis of the Drosophila Citron kinase, Sticky, in Schneider's S2 cells. We define two separable and redundant RhoGEF/Pebble-dependent inputs into Sticky recruitment to the nascent MR and show that each input is subsequently required for retention at, and for the integrity of, the mature MR. The first input is via an actomyosin-independent interaction between Sticky and Anillin, a key scaffold also required for MR formation. The second input requires the Rho-binding domain of Sticky, whose boundaries we have defined. Collectively, these results show how MR biogenesis depends on the coordinated actions of Sticky, Anillin and Rho.
Cytokinesis is driven by a contractile ring whose key components are well-defined. Yet how they are organized and how the contractile ring assembles and constricts, remain unclear. This study combines confocal and super resolution imaging of endogenous contractile ring components in sea urchin embryos ( in vivo) and isolated embryo cortices ( ex vivo), to demonstrate that anillin and septin2 assemble into myosin II-positive clusters. The authors surmise that these clusters are precursors to the contractile ring and observe septin filament nanostructure for the first time in an animal cell contractile ring. These insights into the organization of lesser studied yet conserved contractile ring proteins, anillin and septins, provide clues to their function and pave the way for similar studies in other animal species.
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