Research progress of the transcription factor Brn4 (Review)

Wu, Yuying; Zhang, Xunrui; Wang, Jue; Jin, Guohua; Zhang, Xinhua

doi:10.3892/mmr.2020.11818

Cited by 5 publications

(3 citation statements)

References 86 publications

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“…Because the SrC switch reversibly controls transgene expression for the SeVdp vector, we wished to know if the SrC switch is applicable to direct reprogramming mediated by a transcription factor. To this end, we chose neural cell differentiation from embryonic stem cells (ESCs) as a model system and focused on BRN4, a POU domain transcription factor that plays important roles in development of the nervous system [ 52 ]. BRN4 facilitates direct reprogramming of fibroblasts to neural stem cells (NSCs) together with SOX2, KLF4, and c-MYC [ 53 ].…”

Section: Resultsmentioning

confidence: 99%

An engineered ligand-responsive Csy4 endoribonuclease controls transgene expression from Sendai virus vectors

Kishimoto,

Nishimura,

Morishita

et al. 2024

J Biol Eng

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Background Viral vectors are attractive gene delivery vehicles because of their broad tropism, high transduction efficiency, and durable expression. With no risk of integration into the host genome, the vectors developed from RNA viruses such as Sendai virus (SeV) are especially promising. However, RNA-based vectors have limited applicability because they lack a convenient method to control transgene expression by an external inducer. Results We engineered a Csy4 switch in Sendai virus-based vectors by combining Csy4 endoribonuclease with mutant FKBP12 (DD: destabilizing domain) that becomes stabilized when a small chemical Shield1 is supplied. In this Shield1-responsive Csy4 (SrC) switch, Shield1 increases Csy4 fused with DD (DD-Csy4), which then cleaves and downregulates the transgene mRNA containing the Csy4 recognition sequence (Csy4RS). Moreover, when Csy4RS is inserted in the viral L gene, the SrC switch suppresses replication and transcription of the SeV vector in infected cells in a Shield1-dependent manner, thus enabling complete elimination of the vector from the cells. By temporally controlling BRN4 expression, a BRN4-expressing SeV vector equipped with the SrC switch achieves efficient, stepwise differentiation of embryonic stem cells into neural stem cells, and then into astrocytes. Conclusion SeV-based vectors with the SrC switch should find wide applications in stem cell research, regenerative medicine, and gene therapy, especially when precise control of reprogramming factor expression is desirable.

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Section: Resultsmentioning

confidence: 99%

An engineered ligand-responsive Csy4 endoribonuclease controls transgene expression from Sendai virus vectors

Kishimoto,

Nishimura,

Morishita

et al. 2024

J Biol Eng

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“…(Fig. 6C), which are involved in nervous system development [38][39][40] but have diverse downstream functions (Fig. 6D).…”

Section: Potential Regulatory Mechanisms Of Intergenerational Inherit...mentioning

confidence: 99%

Transcriptomic Effects of Paternal Cocaine-seeking on the Reward Circuitry of Male Offspring

Le,

Huang,

Cui

et al. 2023

Preprint

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In previous research, it has been established that a strong incentive motivation for cocaine, rather than the drug itself, can contribute to the intergenerational inheritance of cocaine addiction susceptibility in descendants. However, the precise impact of paternal cocaine-seeking on the reward circuitry of offspring remains not fully elucidated. To differentiate between cocaine-exposure and cocaine-seeking factors, we employed two distinct paternal cocaine acquisition paradigms: cocaine self-administration and yoked administration. These paradigms were used to generate the F1 generation, along with a control group receiving saline treatment. We conducted a comprehensive transcriptomic analysis of the male F1 offspring across seven relevant brain regions, both under drug-naive conditions and after cocaine self-administration. Our study revealed that the orbitofrontal cortex (OFC) exhibited more pronounced transcriptomic changes in response to cocaine-exposure. Conversely, the dorsal hippocampus (dHip), dorsal striatum (dStr), and ventral tegmental area (VTA) showed alterations that were more closely linked to the paternal voluntary cocaine-seeking experience. Based on transcriptomic analysis, measurements of dopamine levels (DOPA), and cellular activation analysis, we propose that the VTA-dStr pathway plays a pivotal role in mediating the effects of paternal voluntary cocaine-seeking on offspring. Furthermore, we identified potential transcriptomic regulatory mechanisms mediated by key transcriptional factors. Our findings provide a comprehensive overview of the transcriptional changes resulting from paternal highly-motivated cocaine-seeking. Importantly, our data highlight vulnerable neurocircuitry and novel gene candidates with therapeutic potential for disrupting the transgenerational inheritance of vulnerability to cocaine addiction.

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“…Lack of POU3F4 expression in the development of the mouse inner ear leads to a defective adhesion of the fibrocytes in the spiral ligament and consequent degeneration of Cx26/Cx30 gap junction plaques in the inner sulcus (Kidokoro et al, 2014), thus explaining the loss of the endocochlear potential and deafness in Pou3f4-deficient mice. Outside of the hearing organ, POU3F4 is mainly expressed in brain (Wu et al, 2021), kidney and pancreas (Naranjo et al, 2010;Tantin, 2013), but its functional role in these organs has not been completely established. The present study was guided by the genetic appraisal of two male patients with mixed HL and IP3 belonging to our Austrian cohort of patients diagnosed with EVA (Roesch et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Novel POU3F4 variants identified in patients with inner ear malformations exhibit aberrant cellular distribution and lack of SLC6A20 transcriptional upregulation

Bernardinelli

Roesch

Simoni

et al. 2022

Front. Mol. Neurosci.

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Hearing loss (HL) is the most common sensory defect and affects 450 million people worldwide in a disabling form. Pathogenic sequence alterations in the POU3F4 gene, which encodes a transcription factor, are causative of the most common type of X-linked deafness (X-linked deafness type 3, DFN3, DFNX2). POU3F4-related deafness is characterized by a typical inner ear malformation, namely an incomplete partition of the cochlea type 3 (IP3), with or without an enlargement of the vestibular aqueduct (EVA). The pathomechanism underlying POU3F4-related deafness and the corresponding transcriptional targets are largely uncharacterized. Two male patients belonging to a Caucasian cohort with HL and EVA who presented with an IP3 were submitted to genetic analysis. Two novel sequence variants in POU3F4 were identified by Sanger sequencing. In cell-based assays, the corresponding protein variants (p.S74Afs*8 and p.C327*) showed an aberrant expression and subcellular distribution and lack of transcriptional activity. These two protein variants failed to upregulate the transcript levels of the amino acid transporter gene SLC6A20, which was identified as a novel transcriptional target of POU3F4 by RNA sequencing and RT-qPCR. Accordingly, POU3F4 silencing by siRNA resulted in downregulation of SLC6A20 in mouse embryonic fibroblasts. Moreover, we showed for the first time that SLC6A20 is expressed in the mouse cochlea, and co-localized with POU3F4 in the spiral ligament. The findings presented here point to a novel role of amino acid transporters in the inner ear and pave the way for mechanistic studies of POU3F4-related HL.

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Research progress of the transcription factor Brn4 (Review)

Cited by 5 publications

References 86 publications

An engineered ligand-responsive Csy4 endoribonuclease controls transgene expression from Sendai virus vectors

An engineered ligand-responsive Csy4 endoribonuclease controls transgene expression from Sendai virus vectors

Transcriptomic Effects of Paternal Cocaine-seeking on the Reward Circuitry of Male Offspring

Novel POU3F4 variants identified in patients with inner ear malformations exhibit aberrant cellular distribution and lack of SLC6A20 transcriptional upregulation

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