Mast4 knockout shows the regulation of spermatogonial stem cell self-renewal via the FGF2/ERM pathway

Lee, Seungjun; Park, Jinah; Lee, Dong-Joon; Otsu, Keishi; Kim, Pyunggang; Mizuno, Seiya; Lee, Min-Jung; Kim, Hyun-Yi; Harada, Hidemitsu; Takahashi, Satoru; Kim, Seong‐Jin; Jung, Han‐Sung

doi:10.1038/s41418-020-00670-2

Cited by 14 publications

(16 citation statements)

References 40 publications

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“…Furthermore, Mast4(−/−) mice exhibited excessive cartilage synthesis and osteopetrosis phenotype (Kim et al, 2022). In addition, Lee et al (2021) revealed that MAST4 is associated with the fibroblast growth factor 2 (FGF2)/ERM pathway and is essential for spermatogenesis in mice.…”

Section: Introductionmentioning

confidence: 99%

De novo variants in MAST4 related to neurodevelopmental disorders with developmental delay and infantile spasms: Genotype-phenotype association

Zhang

Xiao²,

Cao³

et al. 2023

Front. Mol. Neurosci.

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ObjectiveThis study aims to prove that the de novo variants in MAST4 gene are associated with neurodevelopmental disorders (NDD) with developmental delay (DD) and infantile spasm (IS) and to determine the genotype-phenotype correlations.MethodsTrio-based exome sequencing (ES) was performed on the four families enrolled in this study. We collected and systematically reviewed the four probands’ clinical data, magnetic resonance images (MRI), and electroencephalography (EEG). We also carried out bioinformatics analysis by integrating published exome/genome sequencing data and human brain transcriptomic data.ResultsWe described four patients whose median age of seizure onset was 5 months. The primary manifestation was infantile spasms with typical hypsarrhythmia on EEG. Developmental delays or intellectual disabilities varied among the four individuals. Three de novo missense variants in MAST4 gene were identified from four families, including chr5:66438324 (c.2693T > C: p.Ile898Thr) z, chr5:66459419 (c.4412C > T: p.Thr1471Ile), and chr5:66462662 (c.7655C > G:p.Ser2552Trp). The missense variant p.Ile898Thr is mapped to the AGC-kinase C-terminal with phosphatase activity. The other variant p.Ser2552Trp is located in a phosphoserine-modified residue which may affect cell membrane stability and signal transduction. Besides, the variant p.Thr1471Ile is a recurrent site screened out in two unrelated patients. Compared to private mutations (found only in a single family or a small population) of MAST4 in the gnomAD non-neuro subset, all de novo variants were predicted to be damaging or probably damaging through different bioinformatic analyses. Significantly higher CADD scores of the variant p.Thr1471Ile indicate more deleteriousness of the recurrent site. And the affected amino acids are highly conserved across multiple species. According to the Brainspan Atlas database, MAST4 is expressed primarily in the mediodorsal nucleus of the thalamus and medial prefrontal cortex during the prenatal period, potentially contributing to embryonic brain development.ConclusionOur results revealed that the variants of MAST4 gene might lead to neurodevelopmental disorders with developmental delay and infantile spasm. Thus, MAST4 variants should be considered the potential candidate gene in patients with neurodevelopmental disorders clinically marked by infantile spasms.

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Section: Introductionmentioning

confidence: 99%

De novo variants in MAST4 related to neurodevelopmental disorders with developmental delay and infantile spasms: Genotype-phenotype association

Zhang

Xiao²,

Cao³

et al. 2023

Front. Mol. Neurosci.

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“…Numerous studies have shown that Wnt/β-catenin signaling is closely related to stem cell selfrenewal and maintenance in several organs (Kretzschmar and Clevers, 2017;Xu, et al, 2016;Ring, et al, 2014;Nusse, 2008). Moreover, our previous study revealed a failure of spermatogonial stem cell maintenance in the Mast4 KO testis, although the signaling pathway involved is different from DLX3 (Lee, et al, 2020). In addition, considering that no abnormalities were found in the molars where adult stem cells do not exist after their development being completed at the fetal stage, it can be inferred that MAST4 is involved in the maintenance of adult stem cells in several signaling pathways.…”

Section: Discussionmentioning

confidence: 88%

Unraveling the roles of Mast4 in amelogenesis via regulating DLX3 and stem cell maintenance of mouse incisors

Lee

Kim²,

Kim

et al. 2021

Preprint

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Asymmetric division of stem cells allows for maintenance of the cell population and differentiation for harmonious progress. Developing mouse incisors allows for examination of how the stem cell niche employs specific insights into essential phases. Microtubule-associated serine/threonine kinase family member 4 (Mast4) knockout (KO) mice showed abnormal incisor development with weak hardness as the apical bud was reduced and preameloblasts were shifted to the apical side, resulting in Amelogenesis Imperfecta. In addition, Mast4 KO incisors showed abnormal enamel maturation, and stem cell maintenance was inhibited as amelogenesis accelerated. Distal-Less Homeobox 3 (DLX3), known to be a critical factor Tricho-Dento-Osseous (TDO) syndrome, is considered to be responsible for Amelogenesis Imperfecta in humans. MAST4 directly binds to DLX3 and induces phosphorylation at three residues within the nuclear localization sites (NLS) that promote the nuclear translocation of DLX3. MAST4-mediated phosphorylation of DLX3 ultimately controls the transcription of DLX3 target genes, which are carbonic anhydrase and ion transporter genes involved in the pH regulation process during ameloblast maturation. Taken together, our data reveal a novel role of MAST4 as a critical regulator of ameloblast maturation, which controls DLX3 transcriptional activity.

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“…Besides its role as a neuroprotective mediator 49 – 51 , Mast4 has been reported to undergo O-GlcNAc modification, of which global elevation is frequently observed during osteoblast differentiation 52 . In addition, it was demonstrated that Mast4 mediated FGF-2 signaling, known to play a role in bone formation, in Sertoli cells through induction of ERM phosphorylation at serine 367 residue 53 . Meanwhile, the microtubule cytoskeletons have shown to contribute to the osteogenic differentiation of MSCs 54 .…”

Section: Discussionmentioning

confidence: 99%

Mast4 determines the cell fate of MSCs for bone and cartilage development

Kim

Park²,

Lee

et al. 2022

Nat Commun

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Mesenchymal stromal cells (MSCs) differentiation into different lineages is precisely controlled by signaling pathways. Given that protein kinases play a crucial role in signal transduction, here we show that Microtubule Associated Serine/Threonine Kinase Family Member 4 (Mast4) serves as an important mediator of TGF-β and Wnt signal transduction in regulating chondro-osteogenic differentiation of MSCs. Suppression of Mast4 by TGF-β1 led to increased Sox9 stability by blocking Mast4-induced Sox9 serine 494 phosphorylation and subsequent proteasomal degradation, ultimately enhancing chondrogenesis of MSCs. On the other hand, Mast4 protein, which stability was enhanced by Wnt-mediated inhibition of GSK-3β and subsequent Smurf1 recruitment, promoted β-catenin nuclear localization and Runx2 activity, increasing osteogenesis of MSCs. Consistently, Mast4−/− mice demonstrated excessive cartilage synthesis, while exhibiting osteoporotic phenotype. Interestingly, Mast4 depletion in MSCs facilitated cartilage formation and regeneration in vivo. Altogether, our findings uncover essential roles of Mast4 in determining the fate of MSC development into cartilage or bone.

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Mast4 knockout shows the regulation of spermatogonial stem cell self-renewal via the FGF2/ERM pathway

Cited by 14 publications

References 40 publications

De novo variants in MAST4 related to neurodevelopmental disorders with developmental delay and infantile spasms: Genotype-phenotype association

De novo variants in MAST4 related to neurodevelopmental disorders with developmental delay and infantile spasms: Genotype-phenotype association

Unraveling the roles of Mast4 in amelogenesis via regulating DLX3 and stem cell maintenance of mouse incisors

Mast4 determines the cell fate of MSCs for bone and cartilage development

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