Zebrafish Minichromosome Maintenance Protein 5 Gene Regulates the Development and Migration of Facial Motor Neurons via Fibroblast Growth Factor Signaling

2021 ◽  
pp. 1-11
Author(s):  
Yongmei Wu ◽  
Sizhou Huang ◽  
Haixia Zhao ◽  
Kang Cao ◽  
Jinfan Gan ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Signaling Pathway ◽  
Motor Neurons ◽  
Neural Development ◽  
Fibroblast Growth ◽  
Fgf Signaling ◽  
Minichromosome Maintenance ◽  
Minichromosome Maintenance Protein ◽  
Developmental Features

Minichromosome maintenance protein 5 (MCM5), a member of the microchromosomal maintenance protein family, plays an important role in the initiation and extension of DNA replication. However, its role in neural development in zebrafish remains unclear. Here, we used morpholino (MO) and CRISPR/Cas9 to knock down <i>mcm5</i> and investigated the developmental features of facial motor neurons (FMNs) in the hindbrain of zebrafish. We found that knockdown of <i>mcm5</i> using <i>mcm5</i> MO resulted in a small head, small eyes, and a blurred midbrain-hindbrain boundary, while MO injection of <i>mcm5</i> led to decrease in FMNs and their migration disorder. However, the mutant of <i>mcm5</i> only resulted in the migration defect of FMNs rather than quantity change. We further investigated the underlying mechanism of <i>mcm5</i> in the development of hindbrain using in situ hybridization (ISH) and <i>fgfr1a</i> mRNA co-injected with <i>mcm5</i> MO. Results from ISH showed that the fibroblast growth factor (FGF) signaling pathway was changed when the MCM5 function was lost, with the decrease in <i>fgfr1a</i> and the increase in <i>fgf8</i>, while that of <i>pea3</i> had opposite trend. FMN development defects were rescued by <i>fgfr1a</i> mRNA co-injected with <i>mcm5</i> MO. Our results demonstrated that FGF signaling pathway is required for FMN development in zebrafish. Specifically, <i>mcm5</i> regulates FMN development during zebrafish growing.

scholarly journals Targeting of FGF-Signaling Re-Sensitizes Gastrointestinal Stromal Tumors (GIST) to Imatinib In Vitro and In Vivo

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2643 ◽  
Author(s):  
Sergei Boichuk ◽  
Aigul Galembikova ◽  
Pavel Dunaev ◽  
Ekaterina Micheeva ◽  
Elena Valeeva ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Signaling Pathway ◽  
Tumor Size ◽  
Human Cancer ◽  
Fibroblast Growth ◽  
Ki 67 ◽  
Inhibition Of Proliferation ◽  
Fgfr Signaling

Dysregulation of the fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) signaling pathway is frequently observed in multiple human malignancies, and thus, therapeutic strategies targeting FGFs and FGFRs in human cancer are being extensively explored. We observed the activation of the FGF/FGFR-signaling pathway in imatinib (IM)-resistant gastrointestinal stromal tumor (GIST) cells. Furthermore, we found that the activation of FGFR signaling has a significant impact on IM resistance in GISTs in vitro. Next, we tested the efficacy of BGJ398, a potent and selective FGFR1–3 inhibitor, in xenograft models of GISTs exhibiting secondary IM resistance due to receptor-tyrosine kinase (RTK) switch (loss of c-KIT/gain of FGFR2a). Five to eight-week-old female nu/nu mice were subcutaneously inoculated into the flank areas with GIST T-1R cells. Mice were randomized as control (untreated), IM, BGJ398, or a combination and treated orally for 12 days. IM had a moderate effect on tumor size, thus revealing GIST resistance to IM. Similarly, a minor regression in tumor size was observed in BGJ398-treated mice. Strikingly, a 90% decrease in tumor size was observed in mice treated with a combination of IM and BGJ398. Treatment with BGJ398 and IM also induced major histopathologic changes according to a previously defined histopathologic response score and resulted in massive myxoid degeneration. This was associated with increased intratumoral apoptosis as detected by immunohistochemical staining for cleaved caspase-3 on day 5 of the treatment. Furthermore, treatment with BGJ398 and IM significantly reduced the proliferative activity of tumor cells as measured by positivity for Ki-67 staining. In conclusion, inhibition of FGFR signaling substantially inhibited the growth of IM-resistant GISTs in vitro and showed potent antitumor activity in an IM-resistant GIST model via the inhibition of proliferation, tumor growth, and the induction of apoptosis, thereby suggesting that patients with advanced and metastatic GISTs exhibiting IM resistance might benefit from therapeutic inhibition of FGFR signaling.

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