PLZF Regulates Fibroblast Growth Factor Responsiveness and Maintenance of Neural Progenitors

Gaber, Zachary B.; Butler, Samantha J.; Novitch, Bennett G.

doi:10.1371/journal.pbio.1001676

Cited by 40 publications

(59 citation statements)

References 85 publications

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“…PLZF is also expressed in dividing progenitors and downregulated during neural differentiation . In Drosophila, the PLZF ortholog tramtrack blocks neuronal differentiation and regulates glial development from neural progenitors .…”

Section: Stem Cell Self‐renewalmentioning

confidence: 99%

Concise Review: Balancing Stem Cell Self-Renewal and Differentiation with PLZF

et al. 2016

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In recent years, the highly conserved promyelocytic leukemia zinc finger (PLZF, also known as ZBTB16, ZNF145) has attracted attention as a multifunctional transcription factor involved in major biological processes during development. As a transcription factor, PLZF shows tight regulation in its cell-type-specific and stage-specific expression patterns. Emerging evidence shows that PLZF regulates the balance of self-renewal and differentiation in stem cells. However, the gene regulatory network of PLZF is only beginning to be understood. In this review, we discuss the diverse functions of PLZF, in particular its role in self-renewal versus differentiation of stem cells. We also discuss the current state of knowledge on the gene regulatory network of PLZF, in conjunction with its upstream factors, post-translational modifications and binding cofactors for multiprotein complexes. This review aims to provide the reader with an in-depth understanding of the molecular mechanisms underlying PLZF and the potential applications in tissue regeneration. STEM CELLS 2016;34:277-287 SIGNIFICANCE STATEMENTSIGNIFICANCE STATEMENT Stem cells posses the unique ability to maintain multipotency and selfrenew. Stem cell fate decisions, to self-renew or differentiate, is a key step in the therapeutic use of stem cells for regenerative medicine. In recent years, the highly conserved promyelocytic leukemia zinc finger (PLZF, also known as ZBTB16, ZNF145) has attracted attention as a multifunctional transcription factor involved in stem cell biology. PLZF is expressed in long-term HSCs (LT-HSCs), spermatogonial stem cells and neural progenitors to maintain their selfrenewal. Interestingly, PLZF is also expressed during myeloid differentiation, na€ ıve T cells differentiating into effector T cells, and osteochondral differentiation of MSCs into bone and cartilage. Our labs have substantial experience with the effects of PLZF on the osteochondral differentiation of MSCs, and we would like to propose a model for how PLZF might balance stem cell self-renewal and differentiation as a transcription factor.

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Section: Stem Cell Self‐renewalmentioning

confidence: 99%

Concise Review: Balancing Stem Cell Self-Renewal and Differentiation with PLZF

et al. 2016

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“…Positioned within the C‐terminal region of PLZF, the nine C2H2 zinc finger motifs facilitate direct sequence‐specific DNA binding to target genes. Cell and signaling context dependent, PLZF can serve as a transcriptional activator or repressor (Fahnenstich et al, ; Gaber, Butler, & Novitch, ; Ikeda et al, ; Kommagani et al, ; Labbaye et al, ; Liu et al, ; Mao et al, ; Singh et al, ; Suliman et al, ; Szwarc et al, ; Wang et al, ). Given its pleiotropic effects, PLZF drives a broad spectrum of developmental processes and physiological responses, including limb skeletal patterning, innate immune cell development, hematopoiesis, and spermatogenesis; reviewed in Suliman et al ().…”

Section: Introductionmentioning

confidence: 99%

“…The Plzf KO mouse exhibits homeotic‐like anterior‐to‐posterior transformations in the axial and appendicular skeleton, causing hindlimb abnormalities such as fused or extra digits, loss of the tibia or conversion of the fibula to a tibia‐like structure, and kinked tails (Barna et al, ). Subsequent analysis also revealed that these mutant mice exhibit impairments in the development of hematopoietic stem cell and neural progenitors (Gaber et al, ; Vincent‐Fabert et al, ), in spermatogonial self‐renewal (Buaas et al, ; Costoya et al, ), and in development of innate‐like features of invariant natural killer T (iNKT) cells (Kovalovsky et al, ; Savage et al, ; Savage, Constantinides, & Bendelac, ; Xu et al, ). Important from a translational perspective, many of these phenotypes also arise in humans with loss‐of‐function PLZF mutations (Fischer et al, ), highlighting the evolutionary conserved role of PLZF.…”

Section: Introductionmentioning

confidence: 99%

Using CRISPR/Cas9 engineering to generate a mouse with a conditional knockout allele for the promyelocytic leukemia zinc finger transcription factor

Long

Szwarc

Lanza

et al. 2019

Genesis

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Summary The promyelocytic leukemia zinc finger (PLZF) transcription factor mediates a wide‐range of biological processes. Accordingly, perturbation of PLZF function results in a myriad of physiologic defects, the most conspicuous of which is abnormal skeletal patterning. Although whole body knockout of Plzf in the mouse (Plzf KO) has significantly expanded our understanding of Plzf function in vivo, a conditional knockout mouse model that enables tissue or cell‐type specific ablation of Plzf has not been developed. Therefore, we used CRISPR/Cas 9 gene editing to generate a mouse model in which exon 2 of the murine Plzf gene is specifically flanked (or floxed) by LoxP sites (Plzf f/f). Crossing our Plzf f/f mouse with a global cre‐driver mouse to generate the Plzf d/d bigenic mouse, we demonstrate that exon 2 of the Plzf gene is ablated in the Plzf d/d bigenic. Similar to the previously reported Plzf KO mouse, the Plzf d/d mouse exhibits a severe defect in skeletal patterning of the hindlimb, indicating that the Plzf f/f mouse functions as designed. Therefore, studies in this short technical report demonstrate that the Plzf f/f mouse will be useful to investigators who wish to explore the role of the Plzf transcription factor in a specific tissue or cell‐type.

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“…These data could be explained by the heterogeneity of reprogrammed BSKM LT hiNSCs, which represent distinct regional identities and developmental stages of NSCs. Despite the heterogeneous identity of BSKM LT hiNSCs, all BSKM LT hiNSC lines from distinct origins were negative for PLZF, a transcription factor that functions in early neurodevelopment and disappears in the late stage of neurodevelopment (35), supporting that BSKM LT hiNSCs more likely represent late-stage radial glial cells in developing brain (Fig. 1D, Supplementary Fig.…”

Section: Robust and Reproducible Generation Of Hinscsmentioning

confidence: 77%

Robust and Reproducible Generation of Induced Neural Stem Cells from Human Somatic Cells by Defined Factors

Kwak

Hali

Kim

et al. 2020

IJSC

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Background and Objectives: Recent studies have described direct reprogramming of mouse and human somatic cells into induced neural stem cells (iNSCs) using various combinations of transcription factors. Although iNSC technology holds a great potential for clinical applications, the low conversion efficiency and limited reproducibility of iNSC generation hinder its further translation into the clinic, strongly suggesting the necessity of highly reproducible method for human iNSCs (hiNSCs). Thus, in orderto develop a highly efficient and reproducible protocol for hiNSC generation, we revisited the reprogramming potentials of previously reported hiNSC reprogramming cocktails by comparing the reprogramming efficiency of distinct factor combinations including ours. Methods: We introduced distinct factor combinations, OSKM (OCT4+SOX2+KLF4+C-MYC), OCT4 alone, SOX2 alone, SOX2+HMGA2, BRN4+SKM+SV40LT (BSKM LT ), SK LT , SM LT , and SKM LT and performed comparative analysis of reprogramming potentials of distinct factor combinations in hiNSC generation. Results: Here we show that ectopic expression of five reprogramming factors, BSKM LT leads the robust hiNSC generation (>80 folds enhanced efficiency) from human somatic cells compared with previously described factor combinations. With our combination, we were able to observe hiNSC conversion within 7 days of transduction. Throughout further optimization steps, we found that both BRN4 and KLF4 are not essential for hiNSC conversion. Conclusions: Our factor combination could robustly and reproducibly generate hiNSCs from human somatic cells with distinct origins. Therefore, our novel reprogramming strategy might serve as a useful tool for hiNSC-based clinical application.

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PLZF Regulates Fibroblast Growth Factor Responsiveness and Maintenance of Neural Progenitors

Abstract: A transcription factor called Promyelocytic Leukemia Zinc Finger (PLZF) calibrates the balance between spinal cord progenitor maintenance and differentiation by enhancing their sensitivity to mitogens that are present in developing embryos.

Cited by 40 publications

References 85 publications

Concise Review: Balancing Stem Cell Self-Renewal and Differentiation with PLZF

Concise Review: Balancing Stem Cell Self-Renewal and Differentiation with PLZF

Using CRISPR/Cas9 engineering to generate a mouse with a conditional knockout allele for the promyelocytic leukemia zinc finger transcription factor

Robust and Reproducible Generation of Induced Neural Stem Cells from Human Somatic Cells by Defined Factors

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