Genome Stability by DNA Polymerase β in Neural Progenitors Contributes to Neuronal Differentiation in Cortical Development

Onishi, Kohei; Uyeda, Akiko; Shida, Mitsuhiro; Hirayama, Teruyoshi; Yagi, Takeshi; Yamamoto, Naoya; Sugo, Noriyuki

doi:10.1523/jneurosci.0665-17.2017

“…Regarding DNA repair pathways, it is interesting to note that increased cellular metabolism and transcription frequently lead to DNA damage 54 , 55 . Moreover, disruption of DNA repair machinery in mouse retinal progenitors or cortical progenitors leads to reduced, disturbed trajectories of axon growth and guidance 56 , 57 . Thus, during development, proper axon growth may require efficient DNA repair machinery.…”

Section: Discussionmentioning

confidence: 99%

Co-occupancy identifies transcription factor co-operation for axon growth

Venkatesh

¹

,

Mehra

²

,

Wang

³

et al. 2021

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Transcription factors (TFs) act as powerful levers to regulate neural physiology and can be targeted to improve cellular responses to injury or disease. Because TFs often depend on cooperative activity, a major challenge is to identify and deploy optimal sets. Here we developed a bioinformatics pipeline, centered on TF co-occupancy of regulatory DNA, and used it to predict factors that potentiate the effects of pro-regenerative Klf6 in vitro. High content screens of neurite outgrowth identified cooperative activity by 12 candidates, and systematic testing in a mouse model of corticospinal tract (CST) damage substantiated three novel instances of pairwise cooperation. Combined Klf6 and Nr5a2 drove the strongest growth, and transcriptional profiling of CST neurons identified Klf6/Nr5a2-responsive gene networks involved in macromolecule biosynthesis and DNA repair. These data identify TF combinations that promote enhanced CST growth, clarify the transcriptional correlates, and provide a bioinformatics approach to detect TF cooperation.

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“…Regarding DNA repair pathways, it is interesting to note that increased cellular metabolism and transcription frequently lead to DNA damage 54,55 . Moreover, disruption of DNA repair machinery in mouse retinal progenitors or cortical progenitors leads to reduced, disturbed trajectories of axon growth and guidance 56,57 . Thus during development, proper axon growth may require efficient DNA repair machinery.…”

Section: Discussionmentioning

confidence: 99%

Co-occupancy analysis reveals novel transcriptional synergies for axon growth

Venkatesh

¹

,

Mehra

²

,

Wang

³

et al. 2020

Preprint

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Transcription factors (TFs) act as powerful levers to regulate neural physiology and can be targeted to improve cellular responses to injury or disease. Because TFs often depend on cooperative activity, a major challenge is to identify and deploy optimal sets. Here we developed a novel bioinformatics pipeline, centered on TF co-occupancy of regulatory DNA, and used it to predict factors that improve axon growth in corticospinal tract (CST) axons when combined with a known pro-regenerative TF, Klf6. Assays of neurite outgrowth confirmed cooperative activity by 12 candidates, and in vivo testing showed strong promotion of CST growth upon combined expression of Klf6 and Nr5a2. Transcriptional profiling of CST neurons identified Klf6/Nr5a2-responsive gene networks involved in macromolecule biosynthesis and DNA repair. These data identify novel TF combinations that promote enhanced CST growth, clarify the transcriptional correlates, and provide a bioinformatics roadmap to detect TF synergy. Introduction :As they mature, neurons in the central nervous system (CNS) decline in their capacity for robust axon growth, which broadly limits recovery from injury 1-4 . Axon growth depends on the transcription of large networks of regeneration-associated genes (RAGs), and coaxing activation of these networks in adult CNS neurons is a major unmet goal 2,5 . During periods of developmental axon growth, RAG expression is supported by pro-growth transcription factors (TFs) that bind to relevant promoter and enhancer regions to activate transcription 3,6 . One factor that limits RAG expression in mature neurons is the developmental downregulation of these pro-growth TFs 2,5 . Thus identifying TFs that act developmentally to enable axon growth and supplying them to mature neurons is a promising approach to improve regenerative outcomes in the injured nervous system.An ongoing challenge, however, is to decode the optimal set of factors for axon growth. To date, progress has centered on identifying individual TFs whose ectopic expression in mature neurons leads to improved axon growth. For example, we showed previously that the TF Klf6 is developmentally downregulated and that viral re-expression drives improved axon growth in mature corticospinal neurons, which are critical mediators of fine movement 7 . The restoration of axon growth from this and other single-factor studies remains partial, however, indicating the need for additional intervention. 7-12 . One likely possibility is that because multiple TFs generally act in a coordinated manner to regulate transcription, a more complete restoration of axon growth will depend on multiple TFs. Consistent with this, regeneration competent neurons recruit groups of interacting TFs in the hours to days post-injury, which results in transcriptional remodeling leading to reactivation of growth gene networks and functional recovery [13][14][15] . The need for multi-TF interventions in CNS neurons is recognized conceptually 5,16 , but a major challenge has been to develop a systematic pipeline ...

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“…Polβ gene-null mice die perinatally and exhibit severe nervous system defects mainly due to apoptosis in the CNS and PNS, but the cell deaths of replicating NPCs were, at first, not evaluated [122]. Later, the conditional inactivation of Polβ using distinct forebrain-specific Cre lines revealed frequent DSBs in cortical NPCs during the S-phase, likely due to defective BER in these progenitors [123]. The possible contributions of Polβ-mediated translesion activities and replication stress to the death of these progenitor cells were not considered.…”

Section: Dna Polymerasesmentioning

confidence: 99%

Protective Mechanisms Against DNA Replication Stress in the Nervous System

Charlier

¹

,

Martins

²

2020

Genes

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The precise replication of DNA and the successful segregation of chromosomes are essential for the faithful transmission of genetic information during the cell cycle. Alterations in the dynamics of genome replication, also referred to as DNA replication stress, may lead to DNA damage and, consequently, mutations and chromosomal rearrangements. Extensive research has revealed that DNA replication stress drives genome instability during tumorigenesis. Over decades, genetic studies of inherited syndromes have established a connection between the mutations in genes required for proper DNA repair/DNA damage responses and neurological diseases. It is becoming clear that both the prevention and the responses to replication stress are particularly important for nervous system development and function. The accurate regulation of cell proliferation is key for the expansion of progenitor pools during central nervous system (CNS) development, adult neurogenesis, and regeneration. Moreover, DNA replication stress in glial cells regulates CNS tumorigenesis and plays a role in neurodegenerative diseases such as ataxia telangiectasia (A-T). Here, we review how replication stress generation and replication stress response (RSR) contribute to the CNS development, homeostasis, and disease. Both cell-autonomous mechanisms, as well as the evidence of RSR-mediated alterations of the cellular microenvironment in the nervous system, were discussed.

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Genome Stability by DNA Polymerase β in Neural Progenitors Contributes to Neuronal Differentiation in Cortical Development

Cited by 14 publications

References 79 publications

Co-occupancy identifies transcription factor co-operation for axon growth

Co-occupancy identifies transcription factor co-operation for axon growth

Co-occupancy analysis reveals novel transcriptional synergies for axon growth

Protective Mechanisms Against DNA Replication Stress in the Nervous System

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