The cell fate determinant Scribble is required for maintenance of hematopoietic stem cell function

Mohr, Juliane; Dash, Banaja P; Schnoeder, Tina M.; Wolleschak, Denise; Herzog, Carolin; Santamaria, Nuria Tubio; Weinert, Sönke; Godavarthy, Sonika; Zanetti, Costanza; Naumann, Michael; Hartleben, Björn; Huber, Tobias B.; Krause, Daniela; Kähne, Thilo; Bullinger, Lars; Heidel, Florian H.

doi:10.1038/s41375-018-0025-0

Cited by 22 publications

(14 citation statements)

References 21 publications

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“…Asymmetric cell division and subsequent asymmetric distribu-tion of fate determinants (some shared with fly neuroblasts) both require Scribble function, shaping the relative numbers of different T cell subsets (Pham et al, 2015). Conditional knockout suggests that Scribble plays a similar role in hematopoietic stem cell maintenance (Mohr et al, 2018). In contrast, it does not play a similar role in the erythrocyte lineage (Wölwer et al, 2017).…”

Section: Polarizing Mitosis: Roles For Scribble In Asymmetric Cell Divisionmentioning

confidence: 99%

Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation

Bonello

Peifer

2018

Journal of Cell Biology

121

127

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Key events ranging from cell polarity to proliferation regulation to neuronal signaling rely on the assembly of multiprotein adhesion or signaling complexes at particular subcellular sites. Multidomain scaffolding proteins nucleate assembly and direct localization of these complexes, and the protein Scribble and its relatives in the LAP protein family provide a paradigm for this. Scribble was originally identified because of its role in apical–basal polarity and epithelial integrity in Drosophila melanogaster. It is now clear that Scribble acts to assemble and position diverse multiprotein complexes in processes ranging from planar polarity to adhesion to oriented cell division to synaptogenesis. Here, we explore what we have learned about the mechanisms of action of Scribble in the context of its multiple known interacting partners and discuss how this knowledge opens new questions about the full range of Scribble protein partners and their structural and signaling roles.

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Section: Polarizing Mitosis: Roles For Scribble In Asymmetric Cell Divisionmentioning

confidence: 99%

Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation

Bonello

Peifer

2018

Journal of Cell Biology

121

127

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“…The DNMT3A mutations were previously detected using the MiniSeq System (TruSight Myeloid Sequencing Panel, VariantStudio Software 3.0, Illumina, San Diego, USA). For analysis, murine bone marrow cells were isolated from the femurs as previously described [12]. Bone marrow samples were then assessed for clonal selection of the known DNMT3A mutations by pyrosequencing, according to standard protocols.…”

Section: Patient-derived Xenograft (Pdx) Modelmentioning

confidence: 99%

Prevalence and dynamics of clonal hematopoiesis caused by leukemia-associated mutations in elderly individuals without hematologic disorders

et al. 2020

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Clonal hematopoiesis is frequently observed in elderly people. To investigate the prevalence and dynamics of genetic alterations among healthy elderly individuals, a cohort of 50 people >80 years was genotyped for commonly mutated leukemia-associated genes by targeted deep next-generation sequencing. A total of 16 somatic mutations were identified in 13/50 (26%) individuals. Mutations occurred at low variant allele frequencies (median 11.7%) and remained virtually stable over 3 years without development of hematologic malignancies in affected individuals. With DNMT3A mutations most frequently detected, another cohort of 160 healthy people spanning all age groups was sequenced specifically for DNMT3A revealing an overall mutation rate of 6.2% (13/210) and an age-dependent increase of mutation prevalence. A significant difference (p = 0.017) in the DNMT3A expression pattern was detected between younger and healthy elderly people as determined by qRT-PCR. To evaluate the selection of clonal hematopoietic stem cells (HSCs), bone marrow of two healthy individuals with mutant DNMT3A was transplanted in a humanized mouse model. Xenografts displayed stable kinetics of DNMT3A mutations over 8 months. These findings indicate that the appearance of low-level clones with leukemia-associated mutations is a common age-associated phenomenon, but insufficient to initiate clonal selection and expansion without the additional influence of other factors.

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“…[16][17][18] We and others have shown that HSC maintenance and activity are influenced by several known intrinsic effectors of polarity establishment and asymmetrically associated cell fate determinants. [19][20][21][22] However, not all such factors seem to have the same mechanism or degree of action in mammalian cell types as previously described in model organisms. 23,24 Nonetheless, one study has connected Lis1/Pafah1b1, a dyneinbinding microtubulecapturing and spindle-orienting protein, with its ability to modulate murine HSPC inheritance of cell fate determinants in normal hematopoiesis and leukemia.…”

Section: Introductionmentioning

confidence: 91%

Arhgef2 regulates mitotic spindle orientation in hematopoietic stem cells and is essential for productive hematopoiesis

Chan

Vujovic³

et al. 2021

Blood Advances

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How hematopoietic stem cells (HSCs) coordinate their divisional axis and whether this orientation is important for stem cell–driven hematopoiesis is poorly understood. Single-cell RNA sequencing data from patients with Shwachman-Diamond syndrome (SDS), an inherited bone marrow failure syndrome, show that ARHGEF2, a RhoA-specific guanine nucleotide exchange factor and determinant of mitotic spindle orientation, is specifically downregulated in SDS hematopoietic stem and progenitor cells (HSPCs). We demonstrate that transplanted Arhgef2−/− fetal liver and bone marrow cells yield impaired hematopoietic recovery and a production deficit from long-term HSCs, phenotypes that are not the result of differences in numbers of transplanted HSCs, their cell cycle status, level of apoptosis, progenitor output, or homing ability. Notably, these defects are functionally restored in vivo by overexpression of ARHGEF2 or its downstream activated RHOA GTPase. By using live imaging of dividing HSPCs, we show an increased frequency of misoriented divisions in the absence of Arhgef2. ARHGEF2 knockdown in human HSCs also impairs their ability to regenerate hematopoiesis, culminating in significantly smaller xenografts. Together, these data demonstrate a conserved role for Arhgef2 in orienting HSPC division and suggest that HSCs may divide in certain orientations to establish hematopoiesis, the loss of which could contribute to HSC dysfunction in bone marrow failure.

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The cell fate determinant Scribble is required for maintenance of hematopoietic stem cell function

Cited by 22 publications

References 21 publications

Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation

Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation

Prevalence and dynamics of clonal hematopoiesis caused by leukemia-associated mutations in elderly individuals without hematologic disorders

Arhgef2 regulates mitotic spindle orientation in hematopoietic stem cells and is essential for productive hematopoiesis

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