Lis1 is required for the expansion of hematopoietic stem cells in the fetal liver

Chen, Xufeng; Zhang, Jiali; Zhao, Jingyao; Liu, Haifeng; Sun, Xiang; Zhao, Ming; Liu, Xiaolong

doi:10.1038/cr.2014.69

Cited by 8 publications

(8 citation statements)

References 13 publications

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“…We speculate that such a mechanism might lower the threshold necessary to initiate cell division in the setting of microbial infection, a situation in which the generation of large numbers of antigen-specific T cells may be crucial for host survival. However, despite being capable of cognate antigen-induced proliferation, Lis1-deficient T cells activated in this manner exhibited reduced viability, which may have resulted from cell cycle abnormalities, which have been shown in other cell types lacking Lis1 (11, 33). …”

Section: Discussionmentioning

confidence: 85%

The Microtubule-Associated Protein Lis1 Regulates T Lymphocyte Homeostasis and Differentiation

Ngoi

Lopez

Chang

2016

The Journal of Immunology

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The microtubule-associated protein Lissencephaly 1 (Lis1) is a key regulator of cell division during stem cell renewal and differentiation. In this study, we examined the role of Lis1 in T lymphocyte homeostasis and fate diversification in response to microbial infection. T cell-specific deletion of Lis1 resulted in depletion of the peripheral CD4+ and CD8+ T lymphocyte pool, owing to a loss of homeostatic, cytokine-induced proliferation. By contrast, cognate antigen-triggered proliferation was much less affected, enabling Lis1-deficient CD8+ T cells to differentiate into terminal effector cells in response to microbial infection. Strikingly, however, the specification of Lis1-deficient long-lived memory CD8+ T lymphocytes was impaired due, in part, to an apparent failure to differentiate appropriately to IL-15. Taken together, these findings suggest that Lis1 plays an important role in T cell homeostasis and the generation of memory T lymphocytes.

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Section: Discussionmentioning

confidence: 85%

The Microtubule-Associated Protein Lis1 Regulates T Lymphocyte Homeostasis and Differentiation

Ngoi

Lopez

Chang

2016

The Journal of Immunology

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“…FL-HSCs and adult HSCs differ in terms of cell-cycle dynamics, surface-marker expression, differentiation potential, and geneexpression profile (42)(43)(44)(45). FL-HSCs and adult HSCs might use different mechanisms to control self-renewal and differentiation.…”

Section: Discussionmentioning

confidence: 99%

Uhrf1 controls the self-renewal versus differentiation of hematopoietic stem cells by epigenetically regulating the cell-division modes

Zhao

Chen

Song

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Hematopoietic stem cells (HSCs) are able to both self-renew and differentiate. However, how individual HSC makes the decision between self-renewal and differentiation remains largely unknown. Here we report that ablation of the key epigenetic regulator Uhrf1 in the hematopoietic system depletes the HSC pool, leading to hematopoietic failure and lethality. Uhrf1-deficient HSCs display normal survival and proliferation, yet undergo erythroid-biased differentiation at the expense of self-renewal capacity. Notably, Uhrf1 is required for the establishment of DNA methylation patterns of erythroid-specific genes during HSC division. The expression of these genes is enhanced in the absence of Uhrf1, which disrupts the HSC-division modes by promoting the symmetric differentiation and suppressing the symmetric self-renewal. Moreover, overexpression of one of the up-regulated genes, Gata1, in HSCs is sufficient to phenocopy Uhrf1-deficient HSCs, which show impaired HSC symmetric self-renewal and increased differentiation commitment. Taken together, our findings suggest that Uhrf1 controls the self-renewal versus differentiation of HSC through epigenetically regulating the cell-division modes, thus providing unique insights into the relationship among Uhrf1-mediated DNA methylation, cell-division mode, and HSC fate decision.Uhrf1 | HSCs | epigenetic regulation | cell-division mode | cell fate decision

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“…The microtubule reassembles and contributes to mitotic spindle formation during cell division. Therefore, as a microtubuleassociated protein, Lis1 is also reported to regulate cell division and expansion (17,18,42). Using sequential EdU-BrdU pulsing, we have definitively demonstrated that Lis1 deficiency led to a GC B cell cycle blockade at the G 2 /M phase.…”

Section: Discussionmentioning

confidence: 75%

“…The role of Lis1 in actin polymerization and Ag acquisition seems not able to address why GC B cells were significantly reduced in Lis1 GCB KO mice. We have reported that Lis1 regulates HSC expansion (18). Lis1-deficient HSCs formed multipolar mitotic spindle and showed a cell cycle blockade in the G 2 /M phase, and cells are more prone to apoptosis.…”

Section: Lis1 Deficiency In Gc B Cells Compromises Ab Affinity Maturamentioning

confidence: 95%

“…Lis1 (Pafah1b1) is a microtubule-associated protein implicated in lissencephaly disease (16). We and others have reported previously that by interacting with dynein, Lis1 regulates mitotic spindle orientation or assembly and plays an essential role in expansion of multiple cells, including hematopoietic stem cells (HSCs) (17,18 Rho GTPases, Lis1 also regulates actin-based cytoskeleton in neuron cells (19,20). In this study, we have generated GC B cell-specific Lis1 knockout mice to examine its function in GC reaction.…”

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confidence: 99%

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Lis1 Regulates Germinal Center B Cell Antigen Acquisition and Affinity Maturation

Chen

Cai

Zhang

et al. 2017

The Journal of Immunology

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The germinal center (GC) is the site where activated B cells undergo rapid expansions, somatic hypermutation, and affinity maturation. Affinity maturation is a process of Ag-driven selection. The amount of Ag acquired and displayed by GC B cells determines whether it can be positively selected, and therefore Ag acquisition has to be tightly regulated to ensure the efficient affinity maturation. Cell expansion provides sufficient quantity of GC B cells and Abs, whereas affinity maturation improves the quality of Abs. In this study, we found that Lis1 is a cell-intrinsic regulator of Ag acquisition capability of GC B cells. Lack of Lis1 resulted in redistribution of polymerized actin and accumulation of F-actin at uropod; larger amounts of Ags were acquired and displayed by GC B cells, which presumably reduced the selection stringency. Affinity maturation was thus compromised in Lis1-deficient mice. Consistently, overexpression of Lis1 in GC B cells led to less Ag acquisition and display. Additionally, Lis1 is required for GC B cell expansion, and Lis1 deficiency blocked the cell cycle at the mitotic phase and GC B cells were prone to apoptosis. Overall, we suggest that Lis1 is required for GC B cell expansion, affinity maturation, and maintaining functional intact GC response, thus ensuring both the quantity and quality of Ab response.

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Lis1 is required for the expansion of hematopoietic stem cells in the fetal liver

Cited by 8 publications

References 13 publications

The Microtubule-Associated Protein Lis1 Regulates T Lymphocyte Homeostasis and Differentiation

The Microtubule-Associated Protein Lis1 Regulates T Lymphocyte Homeostasis and Differentiation

Uhrf1 controls the self-renewal versus differentiation of hematopoietic stem cells by epigenetically regulating the cell-division modes

Lis1 Regulates Germinal Center B Cell Antigen Acquisition and Affinity Maturation

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