Safb1 regulates cell fate determination in adult neural stem cells by enhancing Drosha cleavage of NFIB mRNA

During brain homeostasis, stem cell fate determination is crucial to guarantee function, adaptation and regeneration while preventing neurodegeneration and cognitive impairment. How neural stem cells (NSCs) are instructed to generate neurons or glia is not well understood. Here we addressed how fate is resolved in multipotent adult hippocampal NSCs, and identify Scaffold Attachment Factor B1 (Safb1) as a determinant of neuron production by blocking glial commitment. Safb1 is sufficient to block oligodendrocytic differentiation of NSCs by preventing expression of the transcription factor NFIB at the post-transcriptional level. Detailed interrogation of the Drosha interactome and functional validation revealed that Safb1 enhances NFIB mRNA cleavage in a Drosha-dependent fashion. Thus, our study provides a cellular mechanism for selective NSC fate regulation by post-transcriptional destabilization of mRNAs. Given the importance of NSC maintenance and fate determination in the adult brain, our findings have major implications for cell-specific gene expression, brain disease and aging.

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Interaction of Notch Signaling Modulator Numb with α-Adaptin Regulates Endocytosis of Notch Pathway Components and Cell Fate Determination of Neural Stem Cells

Journal of Biological Chemistry ◽

10.1074/jbc.m112.360719 ◽

2012 ◽

Vol 287 (21) ◽

pp. 17716-17728 ◽

Cited By ~ 27

Author(s):

Yan Song ◽

Bingwei Lu

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Notch Signaling ◽

Cell Fate ◽

Notch Pathway ◽

Cell Fate Determination ◽

Fate Determination

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The effect of cofilin 1 expression and phosphorylation dynamics on cell fate determination and neuron maturation in neural stem cells

Neuroscience Letters ◽

10.1016/j.neulet.2021.136292 ◽

2021 ◽

pp. 136292

Author(s):

Xia Jiang ◽

Jianyi lv ◽

Rong Zhou ◽

Xiaoliang Xiang

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Cell Fate ◽

Cell Fate Determination ◽

Fate Determination

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The Effect of Ethanol on Cell Fate Determination of Neural Stem Cells

Alcoholism Clinical and Experimental Research ◽

10.1097/01.alc.0000190658.56149.d4 ◽

2005 ◽

Vol 29 ◽

pp. 225S-229S ◽

Cited By ~ 46

Author(s):

Masaru Tateno ◽

Wataru Ukai ◽

Megumi Yamamoto ◽

Eri Hashimoto ◽

Hiroshi Ikeda ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Cell Fate ◽

Cell Fate Determination ◽

Fate Determination

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POGZ controls embryonic stem cell self-renewal and pluripotency by association with esBAF and HP1

10.1101/2021.02.07.430173 ◽

2021 ◽

Author(s):

Xiaoyun Sun ◽

Linxi Cheng ◽

Yuhua Sun

Keyword(s):

Cell Fate ◽

Neurodevelopmental Disorders ◽

Embryonic Stem ◽

Autism Spectrum ◽

Specific Gene ◽

Open Chromatin ◽

Cell Fate Determination ◽

Chromatin Remodeler ◽

Self Renewal ◽

Fate Determination

AbstractPOGZ, which encodes a multi-domain transcription factor, has been found frequently mutated in neurodevelopmental disorders, particularly autism spectrum disorder (ASD) and intellectual disability (ID). However, little is known about its function in ESC self-renewal and pluripotency, cell fate determination as well as in transcriptional regulation. Here, using embryonic stem cells (ESCs) as model, we show that POGZ plays key roles in the maintenance of ESC and cell fate determination by association with the SWI-SNW chromatin remodeler complex and heterochromatin protein 1 (HP1) proteins. POGZ is essential for the maintenance of ESC undifferentiated state, and loss of POGZ leads to ESC differentiation, likely by up-regulation of primitive endoderm and mesoderm lineage genes and by down-regulation of pluripotency-related genes. Mechanistically, POGZ may control ESC-specific gene expression by association with chromatin remodeler complex esBAF and HP1s, and they can form a PBH triplex. POGZ functions primarily to maintain an open chromatin, as loss of POGZ leads to a reduced chromatin accessibility. Regulation of chromatin under control of POGZ depends on esBAF complex. POGZ is extensively co-localized with OCT4/NANOG genome wide. Taken together, we propose that POGZ is a pluripotency-associated factor, and its absence in ESCs causes failure to maintain a proper ESC-specific chromatin state and transcriptional circuitry of pluripotency, which eventually leads to ESC self-renewal and pluripotency defects. Our work provides important insights into the role of POGZ in ESC self-renewal and pluripotency as well as regulation of transcription, which will be useful for understanding the etiology of neurodevelopmental disorders by POGZ mutation.

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Inhibition of Breast Tumor Stem Cells Expansion by the Endogenous Cell Fate Determination Factor Dachshund

Stem Cells and Cancer Stem Cells, Volume 6 ◽

10.1007/978-94-007-2993-3_34 ◽

2012 ◽

pp. 385-395

Author(s):

Marco Velasco-Velázquez ◽

Kongming Wu ◽

Emanuele Loro ◽

Richard Pestell

Keyword(s):

Stem Cells ◽

Cell Fate ◽

Breast Tumor ◽

Cell Fate Determination ◽

Tumor Stem Cells ◽

Fate Determination

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Do Neural Stem Cells Have a Choice? Heterogenic Outcome of Cell Fate Acquisition in Different Injury Models

International Journal of Molecular Sciences ◽

10.3390/ijms20020455 ◽

2019 ◽

Vol 20 (2) ◽

pp. 455 ◽

Cited By ~ 3

Author(s):

Felix Beyer ◽

Iria Samper Agrelo ◽

Patrick Küry

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Cell Fate ◽

Ex Vivo ◽

Meta Analysis ◽

Cell Types ◽

Adult Brain ◽

Repair Capacity ◽

Cell Fate Decisions ◽

Limiting Parameters

The adult mammalian central nervous system (CNS) is generally considered as repair restricted organ with limited capacities to regenerate lost cells and to successfully integrate them into damaged nerve tracts. Despite the presence of endogenous immature cell types that can be activated upon injury or in disease cell replacement generally remains insufficient, undirected, or lost cell types are not properly generated. This limitation also accounts for the myelin repair capacity that still constitutes the default regenerative activity at least in inflammatory demyelinating conditions. Ever since the discovery of endogenous neural stem cells (NSCs) residing within specific niches of the adult brain, as well as the description of procedures to either isolate and propagate or artificially induce NSCs from various origins ex vivo, the field has been rejuvenated. Various sources of NSCs have been investigated and applied in current neuropathological paradigms aiming at the replacement of lost cells and the restoration of functionality based on successful integration. Whereas directing and supporting stem cells residing in brain niches constitutes one possible approach many investigations addressed their potential upon transplantation. Given the heterogeneity of these studies related to the nature of grafted cells, the local CNS environment, and applied implantation procedures we here set out to review and compare their applied protocols in order to evaluate rate-limiting parameters. Based on our compilation, we conclude that in healthy CNS tissue region specific cues dominate cell fate decisions. However, although increasing evidence points to the capacity of transplanted NSCs to reflect the regenerative need of an injury environment, a still heterogenic picture emerges when analyzing transplantation outcomes in injury or disease models. These are likely due to methodological differences despite preserved injury environments. Based on this meta-analysis, we suggest future NSC transplantation experiments to be conducted in a more comparable way to previous studies and that subsequent analyses must emphasize regional heterogeneity such as accounting for differences in gray versus white matter.

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