Biology subjects
Publications and source records attributed to Ma, X..
The paper with the doi 10.1101/850305 has been removed as a result of a technical error. The paper is available on bioRxiv under this doi: 10.1101/2019.12.14.850305.
The lipopolysaccharide biosynthesis pathway is considered an attractive drug target against the rising threat of multidrug-resistant Gram-negative bacteria. Here, we report two novel small-molecule inhibitors (compounds 1 and 2) of the acyltransferase LpxA, the first enzyme in the lipopolysaccharide biosynthesis pathway. We show genetically that the antibacterial activities of the compounds against efflux-deficient Escherichia coli are mediated by LpxA inhibition. Consistently, the compounds inhibited the LpxA enzymatic reaction in vitro. Intriguingly, using biochemical, biophysical, and structural characterization, we reveal two distinct mechanisms of LpxA inhibition; compound 1 is a substrate-competitive inhibitor targeting apo LpxA and compound 2 is an uncompetitive inhibitor targeting the LpxA-product complex. Compound 2 exhibited more favorable biological and physicochemical properties than compound 1, and was optimized using structural information to achieve improved antibacterial activity against wild type E. coli. These results show that LpxA is a promising antibacterial target and imply the advantages of targeting enzyme-product complexes in drug discovery.
The maternal-to-zygotic transition (MZT) is underpinned by wide-spread transcriptomic and epigenomic remodeling that facilitates totipotency acquisition. Factors regulating MZT vary across species and differences in timing of developmental transitions and motif enrichment at accessible chromatin between human and mouse embryos suggest a distinct regulatory circuitry. Profiling accessible chromatin in bovine preimplantation embryos--timing of developmental transitions in bovine closely resembles that in human--indicated that prior to embryonic genome activation (EGA) accessible chromatin is enriched in maternal transcription factor recognition sites, e.g., CTCF, KLFs, NFY, and SP1, echoing observations in humans and mice, and suggesting that a conserved set of maternal factors regulate chromatin remodeling prior to EGA. In contrast, open chromatin established during EGA was primarily enriched for homeobox motifs and showed remarkable similarities between cattle and humans, indicating that cattle could be a more relevant model for human preimplantation development than mice.
BackgroundSchizophrenia is a complex mental disorder with recent evidence suggesting a critical immune component underpinning its pathophysiology. Two-sample Mendelian randomization (MR) provided an opportunity to probe the immune changes in schizophrenia by harnessing the increasing availability of summary-level data from large GWAS consortia. ObjectiveTo map the extensive immune response of schizophrenia in terms of cytokines/chemokines and to explore the effect of cytokines induced by schizophrenia (SCZ-induced cytokines) on the brain structure and function Sources and methodsUsing the summary-level data generated from GWAS of schizophrenia, cytokines in the peripheral blood and imaging-derived phenotypes (IDPs), we performed two rounds of two-sample MR analysis; the identified cytokines from first round of analysis (schizophrenia => cytokines) were modeled for its underlying structure and subsequent clustering analysis further grouped SCZ-induced cytokines based on their genetic similarities. The multi-phenotype summary statistics of each cytokine module were then used as instrumental variables (IVs) for the second round of MR analysis to detect their effect on brain structure and function. ResultsThe first round of MR analysis identified nine cytokines, the highlight of which includes IL18 (OR = 1.292, P = 8.37 x 10-42) and TNFa (OR = 0.721, P = 7.33 x 10-6), to be causally associated with schizophrenia. These SCZ-induced cytokines could be clustered into three modules. The second round of MR analysis (cytokine module => IDPs) indicated that module B (SCGFb-IP10-CTACK-IL6) significantly increased the level of IDPs including IDP_T1_SIENAX_peripheral_grey_normalised_volume ({beta} = 0.0453, P = 4.40x1010), IDP_dMRI_TBSS_MD_Posterior_corona_radiata_R ({beta}= 0.0584, P = 8.89x 10-16) and IDP_dMRI_TBSS_MD_Cingulum_hippocampus_R ({beta} = 0.0563, P = 9.88x 10-15), with module C (IL18-GROa-TNFa) increasing the level of IDP_dMRI_TBSS_L2_Posterior_thalamic_radiation_R ({beta}= 0.0341, P = 2.67x 10-6). ConclusionOur study, for the first time, mapped the causal link from schizophrenia to the comprehensive immune responses, and the findings suggest immune networks play a role in pathophysiology of schizophrenia by mediating the deviations of total gray matter volume and white matter fibers possibly in the mesolimbic system.
Understanding how prion proteins refold from a cellular isoform (PrPC) to a disease-causing isoform (PrPSc) has been among the "ultimate challenges" in molecular biology, biophysics, pathology, and immunology. Conformational changes of prion proteins from PrPC to PrPSc involve the unfolding of a short -helix that overshadows the challenge. Considering the mechanisms of electrostatic attraction, thermal disturbance, hydrogen ion concentration, hydrophobic interaction, and the shielding effect of water molecules, this study reveals an electrostatic-interaction-based mechanism by means of which prion proteins refold in an aqueous environment. The electrostatic-interaction-induced protein unfolding mechanism causes a hydrophobic polypeptide segment to dangle out over the conglobate main body of the prion protein, thereby allowing the first triangular hydrophobic rung formation via hydrophobic interaction. A molecular model of PrPSc is proposed that allows the {beta}-solenoid with a triangular hydrophobic core. Statement of SignificanceWe present three main results that would revolutionize the understanding of pathology of prion diseases. First, the prion protein refolding (from cellular isoform to scrapie isoform) derives from the unfolding of the shortest -helix of PrPC, which provides a long polypeptide segment full of hydrophobic residues dangling out over the conglobate main body of the prion protein, thereby allowing formation of the first triangular hydrophobic rung via hydrophobic interaction. Second, polyanions-induced increasing in local concentration of hydrogen ion (i.e., the PH increase) undermines the shielding effect of water molecules, thereby allowing escape of the arginine side chains from the hydration shell, destabilizing the shortest -helix and initiating the refolding of PrPC. Third, a {beta}-solenoid structural model for PrPSc with a triangular hydrophobic core is proposed.
A growing number of CRISPR-Cas9 associated applications require co-expression of two distinct gRNAs. However, coexpressing paired gRNAs under the driving of independent but identical promoters in the same direction triggers plasmid instability, due to the presence of direct repeats (DRs). In this study, deletion between DRs occurred with high frequencies during plasmid construction and duplication processes, when three DRs-involved paired-gRNA plasmids cloning strategies were tested. This recombination phenomenon was RecA-independent, in agreement with the replication slippage model. To completely eliminate the DRs-induced plasmid instability, a reversed paired-gRNA plasmids (RPGPs) cloning strategy was developed by converting DRs to the more stable invert repeats (IRs). Using RPGPs, we achieved a rapid deletion of chromosome fragments up to 100 kb with high efficiency of 83.33% in Escherichia coli. This study provides general solutions to construct stable plasmids containing short DRs, which can improve the performances of CRISPR systems that relied on paired gRNAs, and also facilitate other applications involving repeated genetic parts.
PurposeChemotherapy resistance of esophageal cancer is a key factor affecting the postoperative treatment of esophageal cancer. Among the media that transmit signals between cells, the exosomes secreted by tumor cells mediate information transmission between tumor cells, which can make sensitive cells obtain resistance. Although some cellular exosomes play an important role in tumors acquired drug resistance, the related action mechanism is still not explored specifically.\n\nMethodsTo elucidate this process, we constructed a cisplatin-resistant esophageal cancer cell line, and proved that exosomes conferring cellular resistance in esophageal cancer can promote cisplatin resistance in sensitive cells. Through high-throughput sequencing analysis of the exosome and of cells after stimulation by exosomes, we determined that the miRNA193 in exosomes conferring cellular resistance played a key role in sensitive cells acquiring resistance to cisplatin. In vitro experiments showed that miRNA193 can regulate the cell cycle of esophageal cancer cells and inhibit apoptosis, so that sensitive cells can acquire resistance to cisplatin. An in vivo experiment proved that miRNA193 can promote tumor proliferation through the exosomes, and provide sensitive cells with slight resistance to cisplatin.\n\nResultsSmall RNA sequencing of exosomes showed that exosomes in drug-resistant cells have 189 up-regulated and 304 down-regulated miRNAs; transcriptome results showed that drug-resistant cells treated with drug-resistant cellular exosomes have 3446 high-expression and 1709 low-expression genes; correlation analysis showed that drug-resistant cellular exosomes mainly affect the drug resistance of sensitive cells through paths such as cytokine-cytokine receptor interaction, and the VEGF and Jak-STAT signaling pathways; miRNA193, one of the high-expression miRNAs in drug-resistant cellular exosomes, can promote drug resistance by removing cisplatins inhibition of the cell cycle of sensitive cells.\n\nConclusionSensitive cells can become resistant to cisplatin through acquired drug-resistant cellular exosomes, and miRNA193 can make tumor cells acquire cisplatin resistance by regulating the cell cycle.
The active site of the essential, eukaryotic CDK1 kinase is generated by core structural elements, among which the PSTAIRE motif in the critical C-helix, is universally conserved in metazoans. The CDK2 kinase, sharing the PSTAIRE, arose early in metazoan evolution and permitted subdivision of tasks along the S-M-phase axis. The marine chordate, Oikopleura dioica, is the only metazoan known to possess more than a single CDK1 ortholog, and all of its 5 paralogs show sequence divergences in the PSTAIRE. Through assessing CDK1 gene duplications in the appendicularian lineage, we show that the CDK1 activation loop substrate binding platform, ATP entrance site, hinge region, and main Cyclin binding interface, have all diversified under positive selection. Three of the 5 CDK1 paralogs are required for embryonic divisions and knockdown phenotypes illustrate further subdivision of functions along the S-M-phase axis. In parallel to CDK1 gene duplications, there has also been amplification in the Cyclin B complement. Among these, the CDK1d:Cyclin Ba pairing is required for oogenic meiosis and early embryogenesis and shows evidence of coevolution of an exclusive interaction. In an intriguing twist on the general rule that Cyclin B oscillations on a background of stable CDK1 levels regulate M-phase MPF activity, it is CDK1d protein levels that oscillate, rather than Cyclin Ba levels, to drive rapid, early embryonic cell cycles. Strikingly, the modified PSTAIRE of odCDK1d shows convergence over great evolutionary distance with plant CDKB, and in both O. dioica, and plants, these variants exhibit increased specialization to M-phase.
Improving catalytic ability of protein biocatalysts leads to reduction in the production cost of biocatalytic manufacturing process, but the search space of possible proteins/mutants is too large to explore exhaustively through experiments. To some extent, highly soluble recombinant proteins tend to exhibit high activity. Here, we demonstrate that an optimization methodology based on machine learning prediction model can effectively predict which peptide tags can improve protein solubility quantitatively. Based on the protein sequence information, a support vector machine model we recently developed was used to evaluate protein solubility after randomly mutated tags were added to a target protein. The optimization algorithm guided the tags to evolve towards variants that can result in higher solubility. Moreover, the optimization results were validated successfully by adding the tags designed by our optimization algorithm to a model protein, expressing it in vivo and experimentally quantifying its solubility and activity. For example, solubility of a tyrosine ammonium lyase was more than doubled by adding two tags to its N- and C-terminus. Its protein activity was also increased nearly 3.5 fold by adding the tags. Additional experiments also supported that the designed tags were effective for improving activity of multiple proteins and are better than previously reported tags. The presented optimization methodology thus provides a valuable tool for understanding the correlation between amino acid sequence and protein solubility and for engineering protein biocatalysts.\n\nContactkang.zhou@nus.edu.sg, chewxia@nus.edu.sg
Although statistics play a significant role in the medical profession, studying medical statistics is challenging because this topic is more difficult to comprehend than other subjects included in medical curricula. Therefore, improving the teaching of medical statistics to meet the requirements of modern medical students/physicians is an essential task. In this study, based on responses about studying medical statistics completed by medical students, we developed a novel approach to teaching medical statistics named "purpose, database, types of variable, and relationship between variables (PDTR)", which emphasizes how to simply master statistical applications and reduces class hours for students. Also, pilot course was implemented. We discovered that the participants using PDTR performed better on examinations of medical statistics than did graduates of institutions using traditional teaching methods (86.39{+/-}3.72 vs 73.72{+/-}6.58, P < 0.001). In addition, positive feedback was received by participants (>80%). Altogether, as a completely novel pedagogical method of teaching medical statistics, PDTR overcomes the negative attitudes of students towards medical statistics, enhances enthusiasm for learning statistics, and remarkably simplifies the process of studying statistical applications. These advantages are undoubtedly conductive to improving the effective use of medical statistics in physicians professional work.
Tau hyper-phosphorylation and deposition into neurofibrillary tangles have been found in brains of patients with Alzheimers disease (AD) and other tauopathies. Molecular chaperones are involved in regulating the pathological aggregation of phosphorylated Tau (pTau) and modulating disease progression. Here, we report that nicotinamide mononucleotide adenylyltransferase (NMNAT), a well-known NAD synthase, serves as a chaperone of pTau to prevent its amyloid aggregation in vitro as well as mitigate its pathology in a fly tauopathy model. By combining NMR spectroscopy, crystallography, single-molecule and computational approaches, we revealed that NMNAT adopts its enzymatic pocket to specifically bind the phosphorylated sites of pTau, which can be competitively disrupted by the enzymatic substrates of NMNAT. Moreover, we found that NMNAT serves as a co-chaperone of Hsp90 for the specific recognition of pTau over Tau. Our work uncovers a dedicated chaperone of pTau and suggests NMNAT as a key node between NAD metabolism and Tau homeostasis in aging and neurodegeneration.
Whether differences in regulation of protein metabolism and regeneration are involved in the different phenotypic adaptation mechanisms of muscle hypertrophy and atrophy in hibernators? Two fast-type muscles (diaphragm and gastrocnemius) in summer active and hibernating Daurian ground squirrels were selected to detect changes in cross-sectional area (CSA), fiber type distribution, and protein expression indicative of protein synthesis metabolism (protein expression of P-Akt, P-mTORC1, P-S6K1, and P-4E-BP1), protein degradation metabolism (MuRF1, atrogin-1, calpain-1, calpain-2, calpastatin, desmin, troponin T, Beclin1, and LC3-II), and muscle regeneration (MyoD, myogenin, and myostatin). Results showed the CSA of the diaphragm muscle increased significantly by 26.1%, whereas the CSA of the gastrocnemius muscle decreased significantly by 20.4% in the hibernation group compared with the summer active group. Both muscles displayed a significant fast-to-slow fiber-type transition in hibernation. Our study further indicated that increased protein synthesis, decreased protein degradation, and increased muscle regeneration potential contributed to diaphragm muscle hypertrophy, whereas decreased protein synthesis, increased protein degradation, and decreased muscle regeneration potential contributed to gastrocnemius muscle atrophy. In conclusion, the differences in muscle regeneration and regulatory pattern of protein metabolism may contribute to the different adaptive changes observed in the diaphragm and gastrocnemius muscles of ground squirrels.
Pulcherriminic acid, a cyclodipeptide, possesses the excellent antibacterial activities by chelating iron ions from environment, however, the low yield has hindered its application. In this study, high-level production of pulcherriminic acid was achieved by the multistep metabolic engineering of Bacillus licheniformis DWc9n*. Firstly, leucine (Leu) supply was increased by overexpressing the genes ilvBHC-leuABCD and ilvD involved in the Leu synthetic pathway and deleting the gene bkdAB encoding a branched-chain -keto acid dehydrogenase. The intracellular Leu content and pulcherriminic acid yield of strain W2 reached 147.4 mg/g DCW and 189.9 mg/L respectively, which corresponded to a 226.7% and 49.1% higher than those of DWc9n*. Secondly, the strain W3 was obtained by overexpressing leucyl-tRNA synthase LeuS in W2, which lead to a 190% improvement compared to DWc9n*, pulcherriminic acid yield increase to 367.7 mg/L. Thirdly, overexpression of the cytochrome synthase gene cluster yvmC-cypX further increased the yield of pulcherriminic acid to 507.4 mg/L. Finally, the secretion capability was improved by overexpressing the pulcherriminic acid transporter gene yvmA. This resulted in the 556.1 mg/L pulcherriminic acid was produced in W4/pHY-yvmA, increased by 340% as compared with DWc9n*, and it is the highest pulcherriminic acid production currently reported. Taken together, this study provided an efficient strategy for enhancing pulcherriminic acid production and might also be applied for high-level production of other cyclodipeptides.\n\nImportancePulcherriminic acid is a cyclodipeptide that derived from cyclo(L-Leu-L-Leu), which has the same iron chelation group with hydroxamate siderophores. Pulcherriminic acid producing strains can inhibit the growths of various bacteria and plant pathogenic fungi. However, the expected pulcherriminic acid yield was not achieved. This study reports efficient microbial production of pulcherriminic acid in Bacillus licheniformis DWc9n* via multistep metabolic engineering strategies. The combination of these interventions resulted in the establishment of a pulcherriminic acid overproducing strain. In combination with bioprocess engineering efforts, pulcherriminic acid was produced at a final yield of 556 mg/L in a shake flask. This is the highest pulcherriminic acid yield ever reported so far using rationally engineered microbial cell factories.
Emerging evidence has linked the gut microbiota to schizophrenia. However, the functional changes in the gut microbiota and the biological role of individual bacterial species in schizophrenia have not been explored systematically. Here, we characterized the gut microbiota in schizophrenia using shotgun metagenomic sequencing of feces from a discovery cohort of 90 drug-free patients and 81 controls, as well as a validation cohort of 45 patients taking antipsychotics and 45 controls. We screened 83 schizophrenia-associated bacterial species and constructed a classifier comprising 26 microbial biomarkers that distinguished patients from controls with a 0.896 area under the receiver operating characteristics curve (AUC) in the discovery cohort and 0.765 AUC in the validation cohort. Our analysis of fecal metagenomes revealed that schizophrenia-associated gut-brain modules included short-chain fatty acids synthesis, tryptophan metabolism, and synthesis/degradation of neurotransmitters including glutamate, {gamma}-aminobutyric acid, and nitric oxide. The schizophrenia-enriched gut bacterial species include several oral cavity-resident microbes, such as Streptococcus vestibularis. We transplanted Streptococcus vestibularis into the gut of the mice with antibiotic-induced microbiota depletion to explore its functional role. We observed that this microbe transiently inhabited the mouse gut and this was followed by hyperactivity and deficit in social behaviors, accompanied with altered neurotransmitter levels in peripheral tissues. In conclusion, our study identified 26 schizophrenia-associated bacterial species representing potential microbial targets for future treatment, as well as gut-brain modules, some of which may give rise to new microbial metabolites involved in the development of schizophrenia.
BackgroundGiven the struggle in the field of psychiatry to realize the precise diagnosis and treatment, it is in an urgent need to redefine psychiatric disorders based on objective biomarkers. The results generated from large psychiatric genomic consortia show us some new vantage points to understand the pathophysiology of psychiatric disorders. Nevertheless, how to relate these captured signals to the more refined disease dimensions has yet to be established.\n\nMethodsWe chose a top-down, cross-disorder approach by using the summary statistics of GWAS from large psychiatric genomic consortia to build a genomic structural equation model (SEM) for SCZ, BD and MDD to detect their common factor (CF), and to map a potential causal core gene for the CF, followed by the transcriptional prediction of the identified causal gene in our sample and the discovery of new biotypes based on the prediction pattern of the causal gene in the brain. We then characterized the biotypes in the context of their demographic features, cognitive functions and neuroimaging traits.\n\nOutcomesA common factor emerged from a well-fitting genomic SEM of SCZ, BD and MDD (loading 0.42, 0.35 and 0.09 for SCZ, BD and MDD, respectively). One genomic region in chromosome 6 was implicated in the genetic make-up of the common factor, with fine-mapping analysis marking ZNF391 as a potential causal core gene (posterior possibility = 0.96). Gene expression inference analysis identified eight brain regions showing different expression levels of ZNF391 between patients and controls, with three biotypes arising from clustering patients based on their expression pattern of ZNF391 in the brain. The three biotypes performed significantly differently in working memory (PDMS_TC = 0.015, PDMS_TC_A = 0.0318, PDMS_t0D = 0.015) and demonstrated different gray matter volumes in right inferior frontal orbital gyrus (RIFOG) in the same order as working memory (biotype 3 > biotype 2 > biotype 1, PRIFOG = 0.0027). Using ZNF391 as instrumental variable (IV), a partial casual path could be linked from RIFOG to working memory ({beta}RIFOG->DMS_TC0D = 4.95, P = 0.0056; {beta} RIFOG->DMS_TC = 2.53, P = 0.059; {beta}RIFOG->DMS_TC_A = 2.57, P = 0.056).\n\nInterpretationThe general predisposition to several psychiatric disorders may be influenced by variations of ZNF391, through its effects on right inferior frontal orbital gyrus and working memory. This illustrates the potential of a trans-diagnostic, top-down approach in understanding the commonality of psychiatric disorders.\n\nEvidence before this studyThe results from recent cross-disorder genome-wide association studies (GWAS)using large samples indicate that there is notable genetic overlapping between psychiatric disorders. However, the structural relationship of these disorders at the genomic level and the details of refined disease dimensions affected by the associated loci in a cross-disorder pattern remains unknown. We searched the published studies (up to Sep 7, 2019) in PubMed using the combination of the following keywords \"((cross disorder) OR (schizophrenia AND bipolar disorder AND major depressive disorder) AND (genome AND structural equation) AND (cognition OR imaging))\", no published study was found. We then removed the term \"structural equation\", 23 original studies were found. To the best of our knowledge, none of these studies explored the organized structure between three disorders. Further, of 23 articles we found, the majority of them took an approach of either polygenic risk score (PRS) or candidate gene to test the association with either psychological traits such as loneliness or neuroimaging measures in one (schizophrenia) or two (schizophrenia and bipolar) disorders. Hitherto, no study has been conducted to redefine three disorders based on the biological markers generated from the cross-disorder genomic studies.\n\nAdded value of this studyAdopting a novel approach of genomic structural equation modelling, we used the latest results of GWAS of three major psychiatric disorders to detect their common factor, further, to identify the loci associated with such as a common factor, and the locis transcription consequences in the brain. Propelled by the phenomenon \"genes do not read DSM\", we used a cutting-edge clustering algorithm to redefine three disorders based on the cerebral spatial expression pattern of associated core gene. Our study provides another piece of evidence as to the potentials of utilizing the signals arising from large population-scale GWAS to dissect and redefine psychiatric disorders.\n\nImplications of all the available evidenceConsistent with previous case-control cross-disorder GWAS, our study suggests that a common factor exists in three major psychiatric disorders and the biological information of core gene associated with the common factor could be used as an objective marker to explain three disorders and their pathophysiology.
BackgroundSubcortical structures including the basal ganglia have been proposed to be crucial for arousal, consciousness, and behavioural responsiveness. However, how basal ganglia contributes to the loss and recovery of consciousness during anaesthesia has not been well characterized.\n\nMethodsIn this study, using local field potentials (LFPs) from subthalamic nucleus (STN) and scalp electroencephalogram in 12 Parkinsons disease patients, we investigate STN neural signatures during propofol general anaesthesia and during intubation as an arousal intervention in anaesthesia.\n\nResultsPropofol-induced anaesthesia resulted in changes in multiple frequency bands in STN LFPs, including increased low-frequency activities (slow-wave oscillation, delta, theta, and alpha bands) and decreased higher-frequency activities. This was also accompanied by increased STN-frontal cortical coherence in alpha frequency band. Beta and high-gamma activities in the STN temporally increased during intubation compared to the status of loss of consciousness. We also show that the dynamic changes in the high frequency activities (80-180 Hz) in STN LFPs induced by propofol and intubation correlated with power-law exponent in the power spectra between 2 and 80 Hz.\n\nConclusionsOur findings suggest that anaesthesia and intubation induced changes in the STN LFPs in multiple frequency bands. They are also consistent with the hypothesis that the power-law exponent in the power spectra between 2 and 80 Hz reflect the excitation/inhibition balance in the STN, which is modulated by anaesthesia and intubation, and further modulate the high frequency activity.
Photoreceptor cell degeneration is a major cause of blindness and a considerable health burden during aging but effective therapeutic or preventive strategies have not so far become commercially available. Here we show in mouse models that signaling through the tyrosine kinase receptor KIT protects photoreceptor cells against both light-induced and inherited retinal degeneration. Upon light damage, photoreceptor cells upregulate Kit ligand (KITL) and activate KIT signaling, which in turn induces nuclear accumulation of the transcription factor NRF2 and stimulates the expression of the antioxidant gene Hmox1. Conversely, a viable Kit mutation promotes light-induced photoreceptor damage, which is reversed by experimental expression of Hmox1. Furthermore, overexpression of KITL from a viral AAV8 vector prevents photoreceptor cell death and partially restores retinal function after light damage or in genetic models of human retinitis pigmentosa. Hence, application of KITL may provide a novel therapeutic avenue for prevention or treatment of retinal degenerative diseases.
MACF1 is a large crosslinker that contributes to cytoskeleton integrity and cell differentiation. Loss of MACF1 impairs multiple cellular functions in neuron development and epidermal migration, and is the molecular basis for many diseases such as heart failure and Parkinsons disease. MACF1 is highly abundant in bones, however, its involvements in osteogenic differentiation and bone formation are still unknown. In this study, by conditional gene targeting to delete the Macf1 gene specifically in MSCs, we observed ossification retardation and bone loss in MACF1 deficient mice in different developmental stages, which we traced to disorganized cytoskeleton and decreased osteogenic differentiation capability in MSCs. Further, we show that MACF1 interacts and facilitates SMAD7 nuclear translocation to initiate downstream transcription. These findings are hopefully to expand the biological scope of MACF1 in bones, and provide experimental basis for targeting MACF1 in degenerative bone diseases such as osteoporosis.