RESUMEN
The MRTF-SRF pathway has been extensively studied for its crucial role in driving the expression of a large number of genes involved in actin cytoskeleton of various cell types. However, the specific contribution of MRTF-SRF in hair cells remains unknown. In this study, we showed that hair cell-specific deletion of Srf or Mrtfb, but not Mrtfa, leads to similar defects in the development of stereocilia dimensions and the maintenance of cuticular plate integrity. We used fluorescence-activated cell sorting-based hair cell RNA-Seq analysis to investigate the mechanistic underpinnings of the changes observed in Srf and Mrtfb mutants, respectively. Interestingly, the transcriptome analysis revealed distinct profiles of genes regulated by Srf and Mrtfb, suggesting different transcriptional regulation mechanisms of actin cytoskeleton activities mediated by Srf and Mrtfb. Exogenous delivery of calponin 2 using Adeno-associated virus transduction in Srf mutants partially rescued the impairments of stereocilia dimensions and the F-actin intensity of cuticular plate, suggesting the involvement of Cnn2, as an Srf downstream target, in regulating the hair bundle morphology and cuticular plate actin cytoskeleton organization. Our study uncovers, for the first time, the unexpected differential transcriptional regulation of actin cytoskeleton mediated by Srf and Mrtfb in hair cells, and also demonstrates the critical role of SRF-CNN2 in modulating actin dynamics of the stereocilia and cuticular plate, providing new insights into the molecular mechanism underlying hair cell development and maintenance.
Asunto(s)
Citoesqueleto de Actina , Células Ciliadas Auditivas , Células Ciliadas Auditivas/fisiología , Citoesqueleto de Actina/metabolismo , Estereocilios/metabolismo , Actinas/genética , Actinas/metabolismo , Regulación de la Expresión GénicaRESUMEN
OBJECTIVE: To investigated the involvement of pulmonary function impairment in ulcerative colitis (UC), to explore a scientific basis for the Chinese medicine (CM) theory of exterior-interior correlation between Lung (Fei) and Large intestine (Dachang). METHODS: Totally 120 patients with a diagnosis of UC were recruited and the demographics, clinical data, and blood samples were collected. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) concentrations were measured. Every patient accepted pulmonary function test and took chest radiograph (CXR).> RESULTS: Pulmonary function abnormalities were present in 72 of 120 patients. The median (interquartile range) vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), carbon monoxide diffusion capacity (DLCO) of lung, total lung capacity (TLC) and functional residual volume (FRV) were decreased in distal UC and pancolitis compared with ulcerative prochitis (P <0.0005). Male patients had increased VC, FEV1/FVC, and residual volume (RV)/TLC compared with female (P <0.0005), but decreased DLCO and carbon monoxide iffusion capacity (KCO) of lung/alveolar ventilation (P <0.0005). Age was strongly correlated with RV (Spearman rank correlation coefficient (rs)=-0.57,P <0.0001), and RV/TLC (rs=0.48,P<0.0001). Age was also correlated with FEV1/FVC (rs=-0.29, P=0.001), forced expiratory flow in 75% vital capacity (FEF75%, rs=-0.20, P=0.03), DLCO (rs=-0.21, P=0.02), TLC (rs=-0.25, P=0.006), and FRV (rs=-0.28, P=0.002). The course of disease was correlated with FEF75% (rs=-0.18, P=0.049) and KCO (rs=-0.19, P=0.036). Chest radiograph abnormalities were presented in 38 of 120. Pulmonary symptoms were presented in 10 of 120. Other extraintestinal complications were presented in 21 of 120. CONCLUSIONS: Pulmonary function impairment was more frequently than other extraintestinal complications in UC patients, which may be affected by sex, age, extent and course of disease. These results may be a scientific basis for the theory of exterior-interior correlation between Lung and Large intestine.
Asunto(s)
Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/fisiopatología , Colon/patología , Inflamación/complicaciones , Inflamación/patología , Pulmón/fisiopatología , Adolescente , Adulto , Edad de Inicio , Anciano , Colitis Ulcerosa/patología , Demografía , Femenino , Humanos , Pulmón/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Radiografía Torácica , Pruebas de Función Respiratoria , Adulto JovenRESUMEN
OBJECTIVE: To explore the mechanism of pulmonary involvement in ulcerative colitis (UC) patients by observing the correlation between pulmonary functions and levels of alpha1-antitrypsin (A1AT) in serum and colon tissue in UC patients. METHODS: Totally 90 patients with confirmed UC were assigned to different groups according to the extent of disease, the disease activity, the staging of severity, and course of disease. The serum level of A1AT in UC patients with different extent of disease, the disease activity, the staging of severity, and course of disease were compared. And 30 healthy volunteers were recruited as the control group. The serum renal and hepatic functions, pulmonary functions, and serum levels of A1AT were detected in the UC group and the control group. The correlation between A1AT and each pulmonary function index in UC patients was analyzed. The A1AT content in the colon tissue was detected with immunohistochemical assay in 20 UC patients as well as in 10 healthy volunteers. RESULTS: Of the 90 UC patients, 54 patients were accompanied with pulmonary function abnormality (60.0%), and 24 with extraintestinal manifestations (26.7%). Compared with the control group, the serum level of A1AT was significantly lower in the UC group (P < 0.05). The serum level of A1AT was significantly higher in those with proctitis than in those with distal colonitis and pancolitis (P < 0.05). The serum level of A1AT was lower in patients with the course of disease 5 years and more than 5 years than in those with the course of disease less than 5 years (P < 0.05). Vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in one second (FEV1.0), total lung capacity (TLC), function residual volume (FRV), and the ratio of diffusion capacity for carbon monoxide of lung (DLCO) were much lower in those with proctitis than in those with distal colonitis and pancolitis (P < 0.05). The ratio of FVC was negatively linear correlated with the course of disease (r = -0.23, P = 0.018). There was a positive correlation between the serum level of A1AT and peak expiratory flow (PEF) (r = 0.22, P = 0.03). The level of A1AT in the colon tissue was obviously lower in the UC patients than in those of the control group (P < 0.05). Mild and moderate UC patients had increased levels of A1AT in the colon tissue, when compared with severe UC patients (P < 0.05). The level of A1AT in the colon tissue was higher in those with proctitis than in those with distal colonitis and pancolitis (P < 0.05). CONCLUSIONS: The prevalence of pulmonary function impairment was higher than other extraintestinal manifestations in UC patients. The pulmonary function test was helpful to screen the pulmonary impairment of UC patients. The A1AT level in the serum and the colon tissue obviously decreased in UC patients, indicating the pulmonary function impairment of UC patients might manifest as decreased A1AT levels correlated chronic airway inflammation, remodeling of airway, and obstructive changes.