Publications by authors named "Jiangang Gao"

78 Publications

Piccolo is essential for the maintenance of mouse retina but not cochlear hair cell function.

Aging (Albany NY) 2021 Apr 21;13(8):11678-11695. Epub 2021 Apr 21.

School of Life Science and Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan 250100, China.

Piccolo is a presynaptic protein with high conservation among different species, and the expression of Piccolo is extensive in vertebrates. Recently, a small fragment of Piccolo (Piccolino), arising due to the incomplete splicing of intron 5/6, was found to be present in the synapses of retinas and cochleae. However, the comprehensive function of Piccolo in the retina and cochlea remains unclear. In this study, we generated knockout mice using CRISPR-Cas9 technology to explore the function of Piccolo. Unexpectedly, whereas no abnormalities were found in the cochlear hair cells of the mutant mice, significant differences were found in the retinas, in which two layers (the outer nuclear layer and the outer plexiform layer) were absent. Additionally, the amplitudes of electroretinograms were significantly reduced and pigmentation was observed in the fundoscopy of the mutant mouse retinas. The expression levels of Bassoon, a homolog of Piccolo, as well as synapse-associated proteins CtBP1, CtBP2, Kif3A, and Rim1 were down-regulated. The numbers of ribbon synapses in the retinas of the mutant mice were also reduced. Altogether, the phenotype of -/- mice resembled the symptoms of retinitis pigmentosa (RP) in humans, suggesting might be a candidate gene of RP and indicates knockout mice are a good model for elucidating the molecular mechanisms of RP.
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http://dx.doi.org/10.18632/aging.202861DOI Listing
April 2021

Deficiency for Lcn8 causes epididymal sperm maturation defects in mice.

Biochem Biophys Res Commun 2021 Apr 22;548:7-13. Epub 2021 Feb 22.

School of Life Science and Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan, 250100, PR China. Electronic address:

Lipocalin family members, LCN8 and LCN9, are specifically expressed in the initial segment of mouse caput epididymis. However, the biological functions of the molecules in vivo are yet to be clarified. In this study, CRISPR/Cas9 technology was used to generate Lcn8 and Lcn9 knockout mice, respectively. Lcn8 and Lcn9 male mice showed normal spermatogenesis and fertility. In the cauda epididymis of Lcn8 male mice, morphologically abnormal sperm was increased significantly, the proportion of progressive motility sperm was decreased, the proportion of immobilized sperm was elevated, and the sperm spontaneous acrosome reaction (AR) frequency was increased. Conversely, the knockout of Lcn9 did not have any effect on the ratio of morphologically abnormal sperm, sperm motility, and sperm spontaneous AR frequencies. These results demonstrated the role of LCN8 in maintaining the sperm quality in the epididymis, and suggested that the deficiency of LCN8 leads to epididymal sperm maturation defects.
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http://dx.doi.org/10.1016/j.bbrc.2021.02.052DOI Listing
April 2021

Responsive hyaluronic acid-gold cluster hybrid nanogel theranostic systems.

Biomater Sci 2021 Feb;9(4):1363-1373

MOE Key Laboratory of High Performance Polymer Materials and Technology, and Department of Polymer Science & Engineering, College of Chemistry & Chemical Engineering, Nanjing University, Nanjing, 210093, P. R. China.

Tumor microenvironment responsive and self-monitored multimodal synergistic theranostic strategies can significantly improve therapeutic efficacy by overcoming biological barriers. Herein, we report a type of smart fluorescent hyaluronic acid nanogel that can respond to the reducing microenvironment and activate tumor targeting with light-traceable monitoring in cancer therapy. First, the derivative of hyaluronic acid (HA) with a vinyl group and cystamine bisacrylamide were used to synthesize bioreducible HA based nanogels via copolymerization in aqueous medium. Then, multifunctional mHA-gold cluster (mHA-GC) hybrid nanogels were successfully prepared by the in situ reduction of gold salt in the HA nanogels. The HA matrix turns the nanogels into a capsule for effective drug loading with excellent colloidal stability. Interestingly, the reducing tumor microenvironment dramatically enhanced the fluorescence signal of gold clusters in the hybrid nanogels. The highly selective cancer cell uptake and efficient intratumoral accumulation of the hybrid nanogels were demonstrated by fluorescence tracking of these nanogels. Responsive disassembly of the hybrid nanogels and drug release were triggered by excess glutathione presence in cancer cells. Moreover, in vivo and in vitro tumor suppression assays revealed that the doxorubicin-loaded hybrid nanogels exhibited significantly superior tumor cell inhibition abilities compared to free DOX. Overall, the mHA-GC hybrid nanogels emerge as a promising theranostic nanoplatform for the targeted delivery and controlled release of antitumor drugs with light-traceable monitoring in cancer treatment.
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http://dx.doi.org/10.1039/d0bm01815eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934158PMC
February 2021

Liver kinase B1 inhibits smooth muscle calcification via high mobility group box 1.

Redox Biol 2021 01 6;38:101828. Epub 2020 Dec 6.

The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China; School of Pharmacy, Hubei University of Science and Technology, Xianning, Hubei, China. Electronic address:

Vascular calcification is a common pathological feature of atherosclerosis, chronic kidney disease, vascular injury, and aging. Liver kinase B1 (LKB1) plays pivotal roles in cellular processes such as apoptosis, metabolism, and cell cycle regulation. In addition, growing evidence has indicated that LKB1 functions as a tumor suppressor gene. However, its role in vascular calcification has not been reported. LKB1 mice were hybridized with SM22-CreER transgenic mice and adult mice received tamoxifen to obtain smooth muscle-specific LKB1-knockout (LKB1) mice. LKB1 expression was decreased under calcifying conditions, and LKB1 overexpression had a protective effect on vascular calcification. However, high mobility group box 1 (HMGB1) overexpression partially counteracted the promotion of vascular calcification induced by LKB1 overexpression. Mechanically, LKB1 could bind to HMGB1 to promote HMGB1 degradation. Furthermore, LKB1 mice showed intensified vascular calcification, which was alleviated by treatment with the HMGB1 inhibitor glycyrrhizic acid. Based on our results, LKB1 may inhibit vascular calcification via inhibiting HMGB1 expression.
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http://dx.doi.org/10.1016/j.redox.2020.101828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750422PMC
January 2021

WWOX promotes apoptosis and inhibits autophagy in paclitaxel‑treated ovarian carcinoma cells.

Mol Med Rep 2021 02 10;23(2). Epub 2020 Dec 10.

Department of Gynecology and Obstetrics, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China.

Although paclitaxel (PTX) is a first‑line chemotherapeutic agent for the treatment of epithelial ovarian cancer (EOC), its clinical use is restricted by chemoresistance. Autophagy is believed to promote drug resistance, and WW domain‑containing oxidoreductase (WWOX) has been predicted to serve an essential role in apoptosis induction and to suppress autophagy in various tumor cell types. In the present study, the role of WWOX was demonstrated using PTX‑treated EOC cells. Cell viability and apoptosis were detected using Cell Counting Kit‑8, morphological and flow cytometric analyses. WWOX and phosphorylated (p)‑WWOX were highly expressed in PTX‑treated sensitive EOC cells (A2780), which was accompanied by activation of the apoptosis‑related proteins caspase‑3 and poly (ADP‑ribose) polymerase (PARP). Conversely, PTX‑resistant EOC cells (A2780/T) were characterized by reduced WWOX expression and constant phosphorylation levels, as well as undetectable levels of activated caspase‑3 and PARP when cells were treated with PTX. The altered expression of WWOX between the two cell types was further validated by reverse transcription‑-quantitative PCR. The apoptosis‑inducing role of WWOX was also confirmed by flow cytometry after WWOX overexpression was induced in PTX‑treated A2780 cells. These findings indicated that WWOX activation may inhibit chemoresistance and trigger cancer cell death. The upregulated expression levels of the autophagy‑related protein 12‑5 complex, Beclin‑1 and LC3, as well as the downregulation of P62, were also detected following PTX treatment, suggesting that PTX induced autophagic flux in both types of EOC cells. This conclusion was further supported by visualizing the accumulation of autophagosome and autolysosome vesicles, using confocal microscopy and transmission electron microscopy. PTX was also shown to inhibit mTOR signaling, indicated by a decreased level of p‑mTOR and increased expression of eukaryotic translation initiation factor 4E‑binding protein 1. Finally, the interaction between WWOX, mTOR and autophagy was investigated via WWOX transfection experimentation, and indicated that WWOX activated mTOR whilst inhibiting autophagy. These data indicated that WWOX may serve a critical role in PTX‑induced apoptosis and could suppress autophagy by downregulating essential autophagic effectors in EOC cells via mTOR signaling.
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http://dx.doi.org/10.3892/mmr.2020.11754DOI Listing
February 2021

ECRG4 Represses Cell Proliferation and Invasiveness via NFIC/OGN/NF-κB Signaling Pathway in Bladder Cancer.

Front Genet 2020 14;11:846. Epub 2020 Aug 14.

Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China.

Bladder cancer (BCa) is a malignant tumor in the urinary system with high cancer-related mortality worldwide. However, the molecular mechanisms of many genes dysregulated in BCa are still unclear. Herein, we showed that esophageal cancer-related gene-4 (ECRG4), which is downregulated in BCa tissues and cell lines, has a positive correlation with osteoglycin (OGN). Further functional experimental studies suggested that both ECRG4 and OGN inhibit cell proliferation, migration, and invasion in BCa cells. Moreover, ECRG4 acts as a tumor repressor and promotes the expression of OGN via the upregulation of nuclear factor 1 C-type (NFIC), which can bind to the promoter region of OGN and regulate its transcription. Bioinformatics analysis revealed that NFIC is downregulated in BCa tissues and has a positive correlation with ECRG4 or OGN. Esophageal cancer-related gene-4 could positively regulate the protein levels of NFIC in BCa cells. In addition, we demonstrated for the first time that ECRG4 inhibits the nuclear factor (NF)-κB signaling pathway via the upregulation of OGN in BCa cells. Overall, these findings provide evidence that both ECRG4 and OGN function as tumor repressors and that overexpression of ECRG4 inhibits the NF-κB signaling pathway by promoting NFIC/OGN signaling in BCa cells. Our results reveal the molecular regulatory mechanisms of the ECRG4-mediated repression of the NFIC/OGN/NF-κB signaling pathway in BCa and provide potential biomarkers or therapeutic targets for BCa.
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http://dx.doi.org/10.3389/fgene.2020.00846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456849PMC
August 2020

Cdc14a has a role in spermatogenesis, sperm maturation and male fertility.

Exp Cell Res 2020 10 15;395(1):112178. Epub 2020 Jul 15.

School of Life Science and Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan, 250100, PR China. Electronic address:

Cdc14a is an evolutionarily conserved dual-specific protein phosphatase, and it plays different roles in different organisms. Cdc14a mutations in human have been reported to cause male infertility, while the specific role of Cdc14a in regulation of the male reproductive system remains elusive. In the present study, we established a knockout mouse model to study the function of Cdc14a in male reproductive system. Cdc14a male mice were subfertile and they could only produce very few offspring. The number of sperm was decreased, the sperm motility was impaired, and the proportion of sperm with abnormal morphology was elevated in Cdc14a mice. When we mated Cdc14a male mice with wild-type (WT) female mice, fertilized eggs could be found in female fallopian tubes, however, the majority of these embryos died during development. Some empty spaces were observed in seminiferous tubule of Cdc14a testes. Compared with WT male mice, the proportions of pachytene spermatocytes were increased and germ cells stained with γH2ax were decreased in Cdc14a male mice, indicating that knockout of Cdc14a inhibited meiotic initiation. Subsequently, we analyzed the expression levels of some substrate proteins of Cdc14a, including Cdc25a, Wee1, and PR-Set7, and compared those with WT testes, in which the expression levels of these proteins were significantly increased in Cdc14a testes. Our results revealed that Cdc14a male mice are highly subfertile, and Cdc14a is essential for normal spermatogenesis and sperm function.
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http://dx.doi.org/10.1016/j.yexcr.2020.112178DOI Listing
October 2020

Synthesis of cross-linking chitosan-PVA composite hydrogel and adsorption of Cu(II) ions.

Water Sci Technol 2020 Mar;81(5):1063-1070

School of Biochemical and Engineering, Anhui Polytechnic University, Anhui, China E-mail:

A cross-linked chitosan-PVA spherical hydrogel (CSH) was synthesized and its structure was characterized by Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and X-ray diffraction (XRD). The physical and chemical properties of CSH, such as acid resistance and swelling, were determined. Finally, Cu(II) ion removal by the CSH was investigated, and the effects of experimental parameters, including pH, adsorption time, and regeneration performance were examined. Results revealed that CSH has outstanding stability in strong acid solution, thus extending the useful pH range as an adsorbent material. The maximum capacity of CSH for Cu(II) was obtained to be 62.1 mg/g at 25 °C for 24 h. The adsorption process was best described by a pseudo-second-order kinetic model, while isotherm modeling revealed that the Langmuir equation better described the adsorption of Cu(II) on CSH. Moreover, the loaded CSH can be easily regenerated by the HCl-washing method and reused repeatedly for Cu(II) adsorption for up to five cycles.
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http://dx.doi.org/10.2166/wst.2020.204DOI Listing
March 2020

Lethal giant larvae 1 inhibits smooth muscle calcification via high mobility group box 1.

J Mol Cell Cardiol 2020 05 5;142:39-52. Epub 2020 Apr 5.

The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China; School of Pharmacy, Hubei University of Science and Technology, Xianning, Hubei, China. Electronic address:

Vascular calcification is a pathological process closely related to atherosclerosis, diabetic vascular diseases, vascular injury, hypertension, chronic kidney disease and aging. Lethal giant larvae 1 (LGL1) is known as a key regulator of cell polarity and plays an important role in tumorigenesis. However, whether LGL1 regulates vascular calcification remains unclear. In this study, we generated smooth muscle-specific LGL1 knockout (LGL1) mice by cross-breeding LGL1 mice with α-SMA-Cre mice. LGL1 level was significantly decreased during calcifying conditions. Overexpression of LGL1 restrained high phosphate-induced calcification in vascular smooth muscle cells (VSMCs). Mechanically, LGL1 could bind with high mobility group box 1 (HMGB1) and promote its degradation via the lysosomal pathway, thereby inhibiting calcification. Smooth muscle-specific deletion of LGL1 increased HMGB1 level and aggravated vitamin D3-induced vascular calcification, which was attenuated by an HMGB1 inhibitor. LGL1 may inhibit vascular calcification by preventing osteogenic differentiation via promoting HMGB1 degradation.
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http://dx.doi.org/10.1016/j.yjmcc.2020.03.017DOI Listing
May 2020

Elamipretide as a potential candidate for relieving cryodamage to human spermatozoa during cryopreservation.

Cryobiology 2020 08 30;95:138-142. Epub 2020 Mar 30.

Reproductive Medicine Department, Jinan Central Hospital, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China; Reproductive Medicine Department, Jinan Central Hospital Affiliated Shandong University, Jinan, China; Cheeloo College of Medicine, Shandong University, Jinan, China. Electronic address:

As a technique widely used in assisted reproduction, human spermatozoa cryopreservation makes it possible to conserve functional sperm for a long time, but the impact of cryodamage on sperm during the process could not be ignored. The objective of the present study was to investigate the efficacy of Elamipretide, a novel small mitochondrial targeting short cytoprotective peptide, in attenuating cryodamage during spermatozoa cryopreservation. Semen samples were collected and cryopreserved in freeze solution containing different concentrations (0.0, 0.1, 1, and 10 μM) of Elamipretide. Sperm motility, viability, membrane integrity, mitochondrial membrane potential, DNA fragmentation, antioxidant profiles, and acrosome reaction were measured and analyzed. The results showed that supplementation of the freeze media with Elamipretide (1 and 10 μM) significantly improved post-thaw sperm parameters including motility and viability, stability of the plasma membrane, and mitochondria and chromosomes. In addition, by adding Elamipretide, excessive oxidation and acrosome dysfunction in sperm cells undergoing freeze-thaw were also significantly attenuated. Therefore, Elamipretide may be a potential candidate for relieving cryodamage to human spermatozoa during cryopreservation.
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http://dx.doi.org/10.1016/j.cryobiol.2020.03.011DOI Listing
August 2020

Mito-Tempo alleviates cryodamage by regulating intracellular oxidative metabolism in spermatozoa from asthenozoospermic patients.

Cryobiology 2019 12 14;91:18-22. Epub 2019 Nov 14.

Reproductive Medicine Department, Central Hospital Affiliated to Shandong First Medical University, Jinan, China; Cheeloo College of Medicine, Shandong University, Jinan, China. Electronic address:

As the largest proportion of male infertility population, asthenozoospermia patients often resort to sperm cryopreservation to preserve fertility as well as to enrich motile sperm for assisted reproductive techniques (ART), although it may cause some cryodamage during the freezing-thawing process. The objective of this study was to investigate whether mitochondrial antioxidant Mito-Tempo was effective in preventing cryodamage of asthenozoospermic spermatozoa. Asthenozoospermic semen samples were collected and cryopreserved in media supplemented with different concentrations (0.0, 1.0, 10 and 100 μM) of Mito-Tempo. We measured sperm motility, viability, membrane integrity, DNA fragmentation, mitochondrial membrane potential, oxidation product, and antioxidant enzymes activities. Supplementation of the cryopreservation media with Mito-Tempo (10 and 100 μM) induced a significant improvement in sperm viability, motility, membrane integrity, mitochondrial membrane potential and chromatin integrity (P < 0.05). Significant enhancement of antioxidant enzymes activities accompanied by the decreased formation of oxidation products (ROS and MDA) was also observed in groups supplemented with Mito-Tempo (10 and 100 μM). It is concluded that mitochondria targeted antioxidant Mito-Tempo alleviates cryodamage by regulating intracellular oxidative metabolism in spermatozoa from asthenozoospermic patients after cryopreservation.
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http://dx.doi.org/10.1016/j.cryobiol.2019.11.005DOI Listing
December 2019

Elmod3 knockout leads to progressive hearing loss and abnormalities in cochlear hair cell stereocilia.

Hum Mol Genet 2019 12;28(24):4103-4112

Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, Hunan, China.

ELMOD3, an ARL2 GTPase-activating protein, is implicated in causing hearing impairment in humans. However, the specific role of ELMOD3 in auditory function is still far from being elucidated. In the present study, we used the CRISPR/Cas9 technology to establish an Elmod3 knockout mice line in the C57BL/6 background (hereinafter referred to as Elmod3-/- mice) and investigated the role of Elmod3 in the cochlea and auditory function. Elmod3-/- mice started to exhibit hearing loss from 2 months of age, and the deafness progressed with aging, while the vestibular function of Elmod3-/- mice was normal. We also observed that Elmod3-/- mice showed thinning and receding hair cells in the organ of Corti and much lower expression of F-actin cytoskeleton in the cochlea compared with wild-type mice. The deafness associated with the mutation may be caused by cochlear hair cells dysfunction, which manifests with shortening and fusion of inner hair cells stereocilia and progressive degeneration of outer hair cells stereocilia. Our finding associates Elmod3 deficiencies with stereocilia dysmorphologies and reveals that they might play roles in the actin cytoskeleton dynamics in cochlear hair cells, and thus relate to hearing impairment.
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http://dx.doi.org/10.1093/hmg/ddz240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305813PMC
December 2019

Lgl1 deficiency disrupts hippocampal development and impairs cognitive performance in mice.

Genes Brain Behav 2019 11 3;18(8):e12605. Epub 2019 Sep 3.

School of Life Science and Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan, China.

Cellular polarity is crucial for brain development and morphogenesis. Lethal giant larvae 1 (Lgl1) plays a crucial role in the establishment of cell polarity from Drosophila to mammalian cells. Previous studies have found the importance of Lgl1 in the development of cerebellar, olfactory bulb, and cerebral cortex. However, the role of Lgl1 in hippocampal development during the embryonic stage and function in adult mice is still unknown. In our study, we created Lgl1-deficient hippocampus mice by using Emx1-Cre mice. Histological analysis showed that the Emx1-Lgl1 mice exhibited reduced size of the hippocampus with severe malformations of hippocampal cytoarchitecture. These defects mainly originated from the disrupted hippocampal neuroepithelium, including increased cell proliferation, abnormal interkinetic nuclear migration, reduced differentiation, increased apoptosis, gradual disruption of adherens junctions, and abnormal neuronal migration. The radial glial scaffold was disorganized in the Lgl1-deficient hippocampus. Thus, Lgl1 plays a distinct role in hippocampal neurogenesis. In addition, the Emx1-Lgl1 mice displayed impaired behavioral performance in the Morris water maze and fear conditioning test.
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http://dx.doi.org/10.1111/gbb.12605DOI Listing
November 2019

A knock-in mouse model of Pendred syndrome with Slc26a4 L236P mutation.

Biochem Biophys Res Commun 2019 07 30;515(2):359-365. Epub 2019 May 30.

Institute of Developmental Biology, School of Life Science, Shandong University, Jinan, Shandong, China. Electronic address:

SLC26A4 gene mutations lead to Pendred syndrome and non-syndromic hearing loss (DFNB4). The mouse model is well used to study the pathology of Pendred syndrome, however, mice with different Slc26a4 mutations exhibit different phenotypes, and these mice have severe deafness and inner ear malformations that are not imitated less severely Human phenotype. In this study, we generated a knock-in mouse model of Pendred syndrome with Slc26a4 L236P mutation to mimic the most common mutation found in human. Some L236P mice were observed to have significant vestibular dysfunction including torticollis and circling, the giant otoconia and destruction of the otoconial membrane was observed in L236P mice. Unlike other profoundly deafness in Slc26a4 mouse model, L236P mice present mild to profound hearing loss, consistent with the hearing threshold, inner ear hair cells also lost from slight to significant. Together, these data demonstrate that the L236P mouse phenotype is more similar to the human phenotype and should be used as a tool for further research into the human Pendred syndrome.
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http://dx.doi.org/10.1016/j.bbrc.2019.05.157DOI Listing
July 2019

Smooth muscle-specific Gsα deletion exaggerates angiotensin II-induced abdominal aortic aneurysm formation in mice in vivo.

J Mol Cell Cardiol 2019 07 7;132:49-59. Epub 2019 May 7.

The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China. Electronic address:

Objective: Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease without an effective pharmaceutical treatment. Genetic studies have proved the involvement of smooth muscle phenotype switch in the development of AAA. The alpha subunit of the heterotrimeric G stimulatory protein (Gsα) mediates receptor-stimulated production of cyclic adenosine monophosphate (cAMP). However, the role of smooth muscle Gsα in AAA formation remains unknown.

Approach And Results: In this study, mice with knockout of smooth muscle-specific Gsα (Gsα) were generated by cross-breeding Gsα mice with SM22-CreER transgenic mice, induced in adult mice by tamoxifen treatment. Gsα deficiency induced a smooth muscle phenotype switch from a contractile to a synthetic state. Mechanically, Gsα deletion reduced cAMP level and increased the level of human antigen R (HuR), which binds with the adenylate uridylate-rich elements of the 3' untranslated region of Krüppel-like factor 4 (KLF4) mRNA, thereby increasing the stability of KLF4. Moreover, genetic knockdown of HuR or KLF4 rescued the phenotype switch in Gsα-deficient smooth muscle cells. Furthermore, with acute infusion of angiotensin II, the incidence of AAA was markedly higher in ApoE/Gsα than ApoE/Gsα mice and induced increased elastic lamina degradation and aortic expansion. Finally, the levels of Gsα and SM α-actin were significantly lower while those of HuR and KLF4 were higher in human AAA samples than adjacent nonaneurysmal aortic sections.

Conclusions: Gsα may play a protective role in AAA formation by regulating the smooth muscle phenotype switch and could be a potential therapeutic target for AAA disease.
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http://dx.doi.org/10.1016/j.yjmcc.2019.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394040PMC
July 2019

Deletion of Brg1 causes stereocilia bundle fusion and cuticular plate loss in vestibular hair cells.

Hear Res 2019 06 8;377:247-259. Epub 2019 Apr 8.

School of Life Science and Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan, 250100, China. Electronic address:

Brg1 is an ATPase subunit of the SWI/SNF chromatin-remodeling complex, and it is indispensable for the development and homeostasis of various organs. Conditional deletion of Brg1 in cochlea hair cells (HCs) leads to multiple structural defects and profound deafness. However, the premature death of Brg1-deficient cochlea HCs hindered further study of the role of Brg1. In contrast to cochlea HCs, Brg1-deficient vestibular HCs survived for a long time. Therefore, HC apical structure and vestibular function were examined in inner HC-specific conditional Brg1 knockout mice. Vestibular HCs exhibited fused and elongated stereocilia bundles after deletion of Brg1, and the cuticular plate was absent in most HCs with fused stereocilia bundles. HC loss was observed in conditional Brg1 knockout mice at the age of 12 months. Morphological defects and HC loss were primarily restricted in the striolar region of the utricle and saccule and in the central region of ampulla. The behavioral tests revealed that Brg1 deletion in HCs caused vestibular dysfunction in older adult mice. These results suggest that Brg1 may play specific roles in the maintenance of the HC stereocilia bundle and the cuticular plate.
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http://dx.doi.org/10.1016/j.heares.2019.04.002DOI Listing
June 2019

Smooth muscle-specific LKB1 deletion exaggerates angiotensin II-induced abdominal aortic aneurysm in mice.

J Mol Cell Cardiol 2019 05 30;130:131-139. Epub 2019 Mar 30.

The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education,Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China; School of Pharmacy, Hubei University of Science and Technology, Xianning, Hubei, China. Electronic address:

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease without an effective pharmaceutical treatment. Liver kinase B1 (LKB1), a tumor suppressor, is a central regulator of cell polarity and energy homeostasis. However, the role of LKB1 in the development of AAA has not been explored. In this study, mice with knockout of smooth muscle-specific LKB1 (LKB1) were generated by cross-breeding LKB1 mice with SM22-CreER transgenic mice and induced in adult mice by tamoxifen treatment. LKB1 deficiency increased the expression of matrix metalloproteinase 2 (MMP-2), which was inhibited by LKB1 overexpression. Mechanistically, LKB1 could bind to the MMP-2 transcription factor, specificity protein 1 (Sp1), thereby reducing the binding of Sp1 to the MMP-2 promoter to inhibit MMP-2 expression. LKB1 expression was significantly reduced in abdominal aortas of the mouse AAA model. Moreover, smooth muscle-specific LKB1 deletion exaggerated angiotensin II-induced AAA formation accompanied by increased AAA incidence and aortic expansion. Finally, LKB1 level was significantly lower and MMP-2 level higher in human AAA samples than adjacent nonaneurysmal aortic sections. Thus, these results suggest that LKB1 may play a protective role in AAA formation by inhibiting MMP-2 expression and could be a potential therapeutic target for AAA disease.
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http://dx.doi.org/10.1016/j.yjmcc.2019.03.021DOI Listing
May 2019

Loss of Lgl1 Disrupts the Radial Glial Fiber-guided Cortical Neuronal Migration and Causes Subcortical Band Heterotopia in Mice.

Neuroscience 2019 02 28;400:132-145. Epub 2018 Dec 28.

School of Life Science and Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan 250100, China. Electronic address:

Radial glial cells (RGCs) are neuronal progenitors and function as scaffolds for neuronal radial migration in the developing cerebral cortex. These functions depend on a polarized radial glial scaffold, which is of fundamental importance for brain development. Lethal giant larvae 1 (Lgl1), a key regulator for cell polarity from Drosophila to mammals, plays a key role in tumorigenesis and brain development. To overcome neonatal lethality in Lgl1-null mice and clarify the role of Lgl1 in mouse cerebral cortex development and function, we created Lgl1 dorsal telencephalon-specific knockout mice mediated by Emx1-Cre. Lgl1 conditional knockout (CKO) mice had normal life spans and could be used for function research. Histology results revealed that the mutant mice displayed an ectopic cortical mass in the dorsolateral hemispheric region between the normotopic cortex and the subcortical white matter, resembling human subcortical band heterotopia (SBH). The Lgl1 CKO cortex showed disrupted adherens junctions (AJs), which were accompanied by ectopic RGCs and intermediate progenitors, and disorganization of the radial glial fiber system. The early- and late-born neurons failed to reach the destined position along the disrupted radial glial fiber scaffold and instead accumulated in ectopic positions and formed SBH. Additionally, the absence of Lgl1 led to severe abnormalities in RGCs, including hyperproliferation, impaired differentiation, and increased apoptosis. Lgl1 CKO mice also displayed deficiencies in anxiety-related behaviors. We concluded that Lgl1 is essential for RGC development and neural migration during cerebral cortex development.
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http://dx.doi.org/10.1016/j.neuroscience.2018.12.039DOI Listing
February 2019

Multi-stimuli-responsiveness of a novel polydiacetylene-based supramolecular gel.

Soft Matter 2018 Oct;14(39):8044-8050

College of Chemistry and Materials Science, Anhui Normal University, South Jiuhua Rd. 189, Wuhu, Anhui 241002, P. R. China.

Herein, a novel supramolecular gel was fabricated through the bi-component co-assembly strategy of commercially available 10,12-pentacosadiynoic acid (PCDA) and laboratory-synthesized amphiphilic co-gelator N-(2-(1H-imidazol-4-yl)ethyl)stearamide (IMSA), which contains one imidazole head group and a long alkyl chain tail, by synergetic noncovalent interactions. Upon irradiation of normal 254 nm UV light, blue polydiacetylene (PDA) could be obtained by topo-polymerization of the PCDA monomers in the gel phase. This PDA-based supramolecular gel is able to respond to various environmental stimuli and shows a blue-to-red chromatic transition, which could be observed by the naked eye. Specifically, upon exposure to heat, pH, metal cation and organic solvent stimuli, the PDA gel displays thermochromism, halochromism, ionochromism and solvatochromism, respectively. More interestingly, the differences of the above-mentioned stimuli-induced color transition of the blue PDA supramolecular gels could be characterized by UV-Vis absorption spectra and Raman spectra, therefore illuminating a bright application prospect in the area of chemosensing.
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http://dx.doi.org/10.1039/c8sm01515eDOI Listing
October 2018

Tuberous sclerosis complex-mediated mTORC1 overactivation promotes age-related hearing loss.

J Clin Invest 2018 11 24;128(11):4938-4955. Epub 2018 Sep 24.

School of Life Science and Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan, China.

The underlying molecular mechanisms of age-related hearing loss (ARHL) in humans and many strains of mice have not been fully characterized. This common age-related disorder is assumed to be closely associated with oxidative stress. Here, we demonstrate that mTORC1 signaling is highly and specifically activated in the cochlear neurosensory epithelium (NSE) in aging mice, and rapamycin injection prevents ARHL. To further examine the specific role of mTORC1 signaling in ARHL, we generated murine models with NSE-specific deletions of Raptor or Tsc1, regulators of mTORC1 signaling. Raptor-cKO mice developed hearing loss considerably more slowly than WT littermates. Conversely, Tsc1 loss led to the early-onset death of cochlear hair cells and consequently accelerated hearing loss. Tsc1-cKO cochleae showed features of oxidative stress and impaired antioxidant defenses. Treatment with rapamycin and the antioxidant N-acetylcysteine rescued Tsc1-cKO hair cells from injury in vivo. In addition, we identified the peroxisome as the initial signaling organelle involved in the regulation of mTORC1 signaling in cochlear hair cells. In summary, our findings identify overactive mTORC1 signaling as one of the critical causes of ARHL and suggest that reduction of mTORC1 activity in cochlear hair cells may be a potential strategy to prevent ARHL.
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http://dx.doi.org/10.1172/JCI98058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205401PMC
November 2018

Tprn is essential for the integrity of stereociliary rootlet in cochlear hair cells in mice.

Front Med 2019 Dec 30;13(6):690-704. Epub 2018 Aug 30.

School of Life Science, Shandong University, Jinan, 250100, China.

Tprn encodes the taperin protein, which is concentrated in the tapered region of hair cell stereocilia in the inner ear. In humans, TPRN mutations cause autosomal recessive nonsyndromic deafness (DFNB79) by an unknown mechanism. To determine the role of Tprn in hearing, we generated Tprn-null mice by clustered regularly interspaced short palindromic repeat/Cas9 genome-editing technology from a CBA/CaJ background. We observed significant hearing loss and progressive degeneration of stereocilia in the outer hair cells of Tprn-null mice starting from postnatal day 30. Transmission electron microscopy images of stereociliary bundles in the mutant mice showed some stereociliary rootlets with curved shafts. The central cores of the stereociliary rootlets possessed hollow structures with surrounding loose peripheral dense rings. Radixin, a protein expressed at stereocilia tapering, was abnormally dispersed along the stereocilia shafts in Tprn-null mice. The expression levels of radixin and β-actin significantly decreased.We propose that Tprn is critical to the retention of the integrity of the stereociliary rootlet. Loss of Tprn in Tprn-null mice caused the disruption of the stereociliary rootlet, which resulted in damage to stereociliary bundles and hearing impairments. The generated Tprn-null mice are ideal models of human hereditary deafness DFNB79.
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http://dx.doi.org/10.1007/s11684-018-0638-8DOI Listing
December 2019

Knock-In Mice with Myo3a Y137C Mutation Displayed Progressive Hearing Loss and Hair Cell Degeneration in the Inner Ear.

Neural Plast 2018 5;2018:4372913. Epub 2018 Jul 5.

School of Life Science, Shandong University, Jinan 250100, China.

Myo3a is expressed in cochlear hair cells and retinal cells and is responsible for human recessive hereditary nonsyndromic deafness (DFNB30). To investigate the mechanism of DFNB30-type deafness, we established a mouse model of Myo3a kinase domain Y137C mutation by using CRISPR/Cas9 system. No difference in hearing between 2-month-old Myo3a mutant mice and wild-type mice was observed. The hearing threshold of the ≥6-month-old mutant mice was significantly elevated compared with that of the wild-type mice. We observed degeneration in the inner ear hair cells of 6-month-old Myo3a mutant mice, and the degeneration became more severe at the age of 12 months. We also found structural abnormality in the cochlear hair cell stereocilia. Our results showed that Myo3a is essential for normal hearing by maintaining the intact structure of hair cell stereocilia, and the kinase domain plays a critical role in the normal functions of Myo3a. This mouse line is an excellent model for studying DFNB30-type deafness in humans.
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http://dx.doi.org/10.1155/2018/4372913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079384PMC
November 2018

Oocyte-specific deletion of Gα induces oxidative stress and deteriorates oocyte quality in mice.

Exp Cell Res 2018 09 17;370(2):579-590. Epub 2018 Jul 17.

School of Life Science and Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan 250100, PR China. Electronic address:

The stimulatory heterotrimeric G protein alpha subunit (Gα) is a ubiquitous guanine nucleotide-binding protein that regulates the intracellular cAMP signaling pathway and consequently participates in a wide range of biological events. In the reproductive system, despite Gα being associated with oocyte meiotic arrest in vitro, the exact role of Gα in female fertility in vivo remains largely unknown. Here, we generated oocyte-specific Gα knockout mice by using the Cre/LoxP system. We observed that the deletion of Gα caused complete female infertility. Exclusion of post-implantation abnormalities, oogenesis, fertilization, and early embryo development was subsequently monitored; meiosis in Gα-deficient oocytes precociously resumed in only 43% of antral follicles from mutant mice, indicating that alteration of meiotic pause was not the key factor in infertility. Ovulation process and number were normal, but the rate of morphological abnormal oocytes was apparently increased; spindle organization, fertilization, and early embryo development were impaired. Furthermore, the level of ROS (reactive oxygen species) and the mitochondrial aggregation increased, and antioxidant glutathione (GSH) content, ATP level, mtDNA copy number, and mitochondrial membrane potential decreased in Gα-deficient oocytes. GV oocytes from mutant mice showed early-stage apoptosis. Meanwhile, the Gα knockout-induced decline in oocyte quality and low developmental potential was partially rescued by antioxidant supplementation. To sum up, our results are the first to reveal that the profile of Gα oocyte-specific deletion caused female infertility in vivo, and oxidative stress plays an important role in this event.
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http://dx.doi.org/10.1016/j.yexcr.2018.07.023DOI Listing
September 2018

Nigericin Inhibits Epithelial Ovarian Cancer Metastasis by Suppressing the Cell Cycle and Epithelial-Mesenchymal Transition.

Biochemistry (Mosc) 2017 Aug;82(8):933-941

Qilu Hospital, Shandong University, Department of Obstetrics and Gynecology, Jinan, Shandong, 250012, P.R. China.

Epithelial ovarian cancer (EOC) has the highest mortality among various types of gynecological malignancies. Most patients die of metastasis and recurrence due to cisplatin resistance. Thus, it is urgent to develop novel therapies to cure this disease. CCK-8 assay showed that nigericin exhibited strong cytotoxicity on A2780 and SKOV3 cell lines. Flow cytometry indicated that nigericin could induce cell cycle arrest at G0/G1 phase and promote cell apoptosis. Boyden chamber assay revealed that nigericin could inhibit migration and invasion in a dose-dependent manner by suppressing epithelial-mesenchymal transition (EMT) in EOC cells. These effects were mediated, at least partly, by the Wnt/β-catenin signaling pathway. Our results demonstrated that nigericin could inhibit EMT during cell invasion and metastasis through the canonical Wnt/β-catenin signaling pathway. Nigericin may prove to be a novel therapeutic strategy that is effective in patients with metastatic EOC.
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http://dx.doi.org/10.1134/S0006297917080089DOI Listing
August 2017

Loss of Myh14 Increases Susceptibility to Noise-Induced Hearing Loss in CBA/CaJ Mice.

Neural Plast 2016 22;2016:6720420. Epub 2016 Dec 22.

School of Life Science and Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan 250100, China.

MYH14 is a member of the myosin family, which has been implicated in many motile processes such as ion-channel gating, organelle translocation, and the cytoskeleton rearrangement. Mutations in MYH14 lead to a DFNA4-type hearing impairment. Further evidence also shows that MYH14 is a candidate noise-induced hearing loss (NIHL) susceptible gene. However, the specific roles of MYH14 in auditory function and NIHL are not fully understood. In the present study, we used CRISPR/Cas9 technology to establish a Myh14 knockout mice line in CBA/CaJ background (now referred to as Myh14 mice) and clarify the role of MYH14 in the cochlea and NIHL. We found that Myh14 mice did not exhibit significant hearing loss until five months of age. In addition, Myh14 mice were more vulnerable to high intensity noise compared to control mice. More significant outer hair cell loss was observed in Myh14 mice than in wild type controls after acoustic trauma. Our findings suggest that Myh14 may play a beneficial role in the protection of the cochlea after acoustic overstimulation in CBA/CaJ mice.
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http://dx.doi.org/10.1155/2016/6720420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215640PMC
October 2017

Heterotrimeric G Stimulatory Protein α Subunit Is Required for Intestinal Smooth Muscle Contraction in Mice.

Gastroenterology 2017 04 30;152(5):1114-1125.e5. Epub 2016 Dec 30.

The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China. Electronic address:

Background & Aims: The α subunit of the heterotrimeric G stimulatory protein (Gsa), encoded by the guanine nucleotide binding protein, α-stimulating gene (Gnas, in mice), is expressed ubiquitously and mediates receptor-stimulated production of cyclic adenosine monophosphate and activation of the protein kinase A signaling pathway. We investigated the roles of Gsa in vivo in smooth muscle cells of mice.

Methods: We performed studies of mice with Cre recombinase-mediated disruption of Gnas in smooth muscle cells (Gsa and SM22-CreER, induced in adult mice by tamoxifen). Intestinal tissues were collected for histologic, biochemical, molecular, cell biology, and physiology analyses. Intestinal function was assessed in mice using the whole-gut transit time test. We compared gene expression patterns of intestinal smooth muscle from mice with vs without disruption of Gnas. Biopsy specimens from ileum of patients with chronic intestinal pseudo-obstruction and age-matched control biopsies were analyzed by immunohistochemistry.

Results: Disruption of Gnas in smooth muscle of mice reduced intestinal motility and led to death within 4 weeks. Tamoxifen-induced disruption of Gnas in adult mice impaired contraction of intestinal smooth muscle and peristalsis. More than 80% of these died within 3 months of tamoxifen exposure, with features of intestinal pseudo-obstruction characterized by chronic intestinal dilation and dysmotility. Gsa deficiency reduced intestinal levels of cyclic adenosine monophosphate and transcriptional activity of the cyclic adenosine monophosphate response element binding protein 1 (CREB1); this resulted in decreased expression of the forkhead box F1 gene (Foxf1) and protein, and contractile proteins, such as myosin heavy chain 11; actin, α2, smooth muscle, aorta; calponin 1; and myosin light chain kinase. We found decreased levels of Gsa, FOXF1, CREB1, and phosphorylated CREB1 proteins in intestinal muscle layers of patients with chronic intestinal pseudo-obstruction, compared with tissues from controls.

Conclusions: Gsa is required for intestinal smooth muscle contraction in mice, and its levels are reduced in ileum biopsies of patients with chronic intestinal pseudo-obstruction. Mice with disruption of Gnas might be used to study human chronic intestinal pseudo-obstruction.
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http://dx.doi.org/10.1053/j.gastro.2016.12.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430528PMC
April 2017

Loss of liver kinase B1 causes planar polarity defects in cochlear hair cells in mice.

Front Med 2016 Dec 23;10(4):481-489. Epub 2016 Dec 23.

School of Life Science and Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan, 250100, China.

The tumor suppressor gene liver kinase B1 (LKB1), also called STK11, encodes a serine/threonine kinase. LKB1 plays crucial roles in cell differentiation, proliferation, and polarity. In this study, LKB1 conditional knockout mice (LKB1 CKO mice) were generated using Pax2-Cre mice to investigate the function of LKB1 in inner ear hair cells during early embryonic period. LKB1 CKO mice died perinatally. Immunofluorescence and scanning electron microscopy revealed that stereociliary bundles in LKB1 CKO mice were clustered and misoriented, respectively. Moreover, ectopic distribution of kinocilium bundles resulting from abnormal migration of kinocilium was observed in the mutant mice. The orientation of stereociliary bundles and the migration of kinocilia are critical indicators of planar cell polarity (PCP) of hair cells. LKB1 deficiency in LKB1 CKO mice thus disrupted hair cell planar polarity during embryonic development. Our results suggest that LKB1 is required in PCP formation in cochlear hair cells in mice.
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http://dx.doi.org/10.1007/s11684-016-0494-3DOI Listing
December 2016

Sorting nexin 9 (SNX9) is not essential for development and auditory function in mice.

Oncotarget 2016 Oct;7(42):68921-68932

Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Jinan, Shandong 250100, P. R. China.

Sorting nexins are a large family of evolutionarily conserved proteins that play fundamental roles in endocytosis, endosomal sorting and signaling. As an important member of sorting nexin family, sorting nexin 9 (SNX9) has been shown to participate in coordinating actin polymerization with membrane tubulation and vesicle formation. We previously showed that SNX9 is expressed in mouse auditory hair cells and might regulate actin polymerization in those cells. To further examine the physiological role of SNX9, we generated Snx9 knockout mice using homologous recombination method. Unexpectedly, Snx9 knockout mice have normal viability and fertility, and are morphologically and behaviorally indistinguishable from control mice. Further investigation revealed that the morphology and function of auditory hair cells are not affected by Snx9 inactivation, and Snx9 knockout mice have normal hearing threshold. In conclusion, our data revealed that Snx9-deficient mice do not show defects in development as well as auditory function, suggesting that SNX9 is not essential for mice development and hearing.
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http://dx.doi.org/10.18632/oncotarget.12040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356600PMC
October 2016

Loss of Lysyl Oxidase-like 3 Attenuates Embryonic Lung Development in Mice.

Sci Rep 2016 09 20;6:33856. Epub 2016 Sep 20.

School of Life Science and Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan 250100, China.

Lysyl oxidase-like 3 (LOXL3), a human disease gene candidate, is a member of the lysyl oxidase (LOX) family and is indispensable for mouse palatogenesis and vertebral column development. Our previous study showed that the loss of LOXL3 resulted in a severe cleft palate and spinal deformity. In this study, we investigated a possible role for LOXL3 in mouse embryonic lung development. LOXL3-deficient mice displayed reduced lung volumes and weights, diminished saccular spaces, and deformed and smaller thoracic cavities. Excess elastic fibres were detected in LOXL3-deficient lungs, which might be related to the increased LOXL4 expression. Increased transforming growth factor β1 (TGFβ1) expression might be involved in the up-regulation of LOXL4 in LOXL3-deficient lungs. We concluded that the loss of LOXL3 attenuates mouse embryonic lung development.
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http://dx.doi.org/10.1038/srep33856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029289PMC
September 2016