SOX Transcription Factors as Important Regulators of Neuronal and Glial Differentiation During Nervous System Development and Adult Neurogenesis

Stevanović, Milena; Drakulić, Danijela; Lazic, Andrijana; Ninković, Danijela Stanisavljević; Schwirtlich, Marija; Mojsin, Marija

doi:10.3389/fnmol.2021.654031

Cited by 95 publications

(81 citation statements)

References 266 publications

(460 reference statements)

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“…Sox proteins are architectural components of chromatin ( Pevny and Lovell-Badge, 1997 ), which govern neuronal and glial lineage specification during development. In the regenerating adult PNS, Sox members are pioneer TFs that poise downstream TFs for transcriptional regulation ( Stevanovic et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Sexual Dimorphism of Early Transcriptional Reprogramming in Dorsal Root Ganglia After Peripheral Nerve Injury

Chernov

Shubayev

2021

Front. Mol. Neurosci.

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Peripheral nerve injury induces genome-wide transcriptional reprogramming of first-order neurons and auxiliary cells of dorsal root ganglia (DRG). Accumulating experimental evidence suggests that onset and mechanistic principles of post-nerve injury processes are sexually dimorphic. We examined largely understudied aspects of early transcriptional events in DRG within 24 h after sciatic nerve axotomy in mice of both sexes. Using high-depth RNA sequencing (>50 million reads/sample) to pinpoint sexually dimorphic changes related to regeneration, immune response, bioenergy, and sensory functions, we identified a higher number of transcriptional changes in male relative to female DRG. In males, the decline in ion channel transcripts was accompanied by the induction of innate immune cascades via TLR, chemokine, and Csf1-receptor axis and robust regenerative programs driven by Sox, Twist1/2, and Pax5/9 transcription factors. Females demonstrated nerve injury-specific transcriptional co-activation of the actinin 2 network. The predicted upstream regulators and interactive networks highlighted the role of novel epigenetic factors and genetic linkage to sex chromosomes as hallmarks of gene regulation post-axotomy. We implicated epigenetic X chromosome inactivation in the regulation of immune response activity uniquely in females. Sexually dimorphic regulation of MMP/ADAMTS metalloproteinases and their intrinsic X-linked regulator Timp1 contributes to extracellular matrix remodeling integrated with pro-regenerative and immune functions. Lexis1 non-coding RNA involved in LXR-mediated lipid metabolism was identified as a novel nerve injury marker. Together, our data identified unique early response triggers of sex-specific peripheral nerve injury regulation to gain mechanistic insights into the origin of female- and male-prevalent sensory neuropathies.

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Section: Discussionmentioning

confidence: 99%

Sexual Dimorphism of Early Transcriptional Reprogramming in Dorsal Root Ganglia After Peripheral Nerve Injury

Chernov

Shubayev

2021

Front. Mol. Neurosci.

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“…To further explore how these gene expression changes might have happened, we next performed transcription factor (TF) target enrichment analysis to identify potential upstream TFs responsible for observed changes in gene expression of Nutlin-3-treated Fmr1 KO mice. Our analysis showed that the top TFs are mainly involved in stem cell fate specification (such as MEOX1, MEOX2, PRRX1, BNC2, SOX18 and TWIST1) [47][48][49][50][51] and/or extra cellular matrix organization (such as HEYL,TBX18, PRRX1, PRRX2 and TCF21 ) [52][53][54] (Fig. 6a; ;Additional file 3: Fig.…”

Section: Transient Nutlin-3 Treatment Leads To Significant and Specif...mentioning

confidence: 94%

Sustained correction of hippocampal neurogenic and cognitive deficits after a brief treatment by Nutlin-3 in a mouse model of Fragile X Syndrome

Javadi

Shen

et al. 2022

Preprint

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Background: Fragile X syndrome (FXS), the most prevalent inherited intellectual disability and one of the most common monogenic form of autism, is caused by a loss of FMRP translational regulator 1 (FMR1). We have previously shown that FMR1 represses the levels and activities of ubiquitin ligase MDM2 in young adult FMR1-deficient mice and treatment by a MDM2 inhibitor Nutlin-3 rescues both hippocampal neurogenic and cognitive deficits in FMR1-deficient mice when analyzed shortly after the administration. However, it is unknown whether Nutlin-3 treatment can have long-lasting therapeutic effects. Methods: We treated 2-month-old young adult FMR1-deficient mice with Nutlin-3 for 10 days and then assessed the persistent effect of Nutlin-3 on both cognitive functions and adult neurogenesis when mice were 6-month-old mature adults. To investigate the mechanisms underlying persistent effects of Nutlin-3, we analyzed proliferation and differentiation of neural stem cells isolated from these mice and assessed the transcriptome of the hippocampal tissues of treated mice. Results: We found that transient treatment with Nutlin-3 of 2-month-old young adult FMR1-deficient mice prevents the emergence of neurogenic and cognitive deficits in mature adult FXS mice at 6-month of age. We further found that the long-lasting restoration of neurogenesis and cognitive function might not be mediated by changing intrinsic properties of adult neural stem cells. Transcriptomic analysis of the hippocampal tissue demonstrated that transient Nultin-3 treatment leads to significant expression changes in genes related to extracellular matrix, secreted factors, and cell membrane proteins in FMR1-deficient hippocampus.

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“…Disruption of the interactions of transcription factors with the transcription complex results in the downregulation of the selected gene. For example, SRY (sex determining region Y)-box 2, SOX2, is a transcription factor that plays an essential role in early embryonic development and neural differentiation [72]. SOX2 is co-expressed with SYN in the Lewy bodies in the brain of PD patients [73], where SYN is also co-localized with TPPP/p25 [27].…”

Section: Regulation At Gene Level: Transcription Factorsmentioning

confidence: 99%

Challenges in Discovering Drugs That Target the Protein–Protein Interactions of Disordered Proteins

Oláh

Szénási

Lehotzky

et al. 2022

IJMS

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Protein–protein interactions (PPIs) outnumber proteins and are crucial to many fundamental processes; in consequence, PPIs are associated with several pathological conditions including neurodegeneration and modulating them by drugs constitutes a potentially major class of therapy. Classically, however, the discovery of small molecules for use as drugs entails targeting individual proteins rather than targeting PPIs. This is largely because discovering small molecules to modulate PPIs has been seen as extremely challenging. Here, we review the difficulties and limitations of strategies to discover drugs that target PPIs directly or indirectly, taking as examples the disordered proteins involved in neurodegenerative diseases.

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SOX Transcription Factors as Important Regulators of Neuronal and Glial Differentiation During Nervous System Development and Adult Neurogenesis

Cited by 95 publications

References 266 publications

Sexual Dimorphism of Early Transcriptional Reprogramming in Dorsal Root Ganglia After Peripheral Nerve Injury

Sexual Dimorphism of Early Transcriptional Reprogramming in Dorsal Root Ganglia After Peripheral Nerve Injury

Sustained correction of hippocampal neurogenic and cognitive deficits after a brief treatment by Nutlin-3 in a mouse model of Fragile X Syndrome

Challenges in Discovering Drugs That Target the Protein–Protein Interactions of Disordered Proteins

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