The Notch and transforming growth factor-β (TGF-β) signaling pathways play critical roles in the control of cell fate during metazoan development. However, mechanisms of cross-talk and signal integration between the two systems are unknown. Here, we demonstrate a functional synergism between Notch and TGF-β signaling in the regulation of Hes-1, a direct target of the Notch pathway. Activation of TGF-β signaling up-regulated Hes-1 expression in vitro and in vivo. This effect was abrogated in myogenic cells by a dominant-negative form of CSL, an essential DNA-binding component of the Notch pathway. TGF-β regulated transcription from the Hes-1 promoter in a Notch-dependent manner, and the intracellular domain of Notch1 (NICD) cooperated synergistically with Smad3, an intracellular transducer of TGF-β signals, to induce the activation of synthetic promoters containing multimerized CSL- or Smad3-binding sites. NICD and Smad3 were shown to interact directly, both in vitro and in cells, in a ligand-dependent manner, and Smad3 could be recruited to CSL-binding sites on DNA in the presence of CSL and NICD. These findings indicate that Notch and TGF-β signals are integrated by direct protein–protein interactions between the signal-transducing intracellular elements from both pathways.

The bone morphogenetic protein (BMP) and Notch signaling pathways are crucial for cellular differentiation. In many cases, the two pathways act similarly; for example, to inhibit myogenic differentiation. It is not known whether this inhibition is caused by distinct mechanisms or by an interplay between Notch and BMP signaling. Here we demonstrate that functional Notch signaling is required for BMP4-mediated block of differentiation of muscle stem cells, i.e. satellite cells and the myogenic cell line C2C12. Addition of BMP4 during induction of differentiation dramatically reduced the number of differentiated satellite and C2C12 cells. Differentiation was substantially restored in BMP4-treated cultures by blocking Notch signaling using either theγ-secretase inhibitor L-685,458 or by introduction of a dominant-negative version of the Notch signal mediator CSL. BMP4 addition to C2C12 cells increased transcription of two immediate Notch responsive genes, Hes1 and Hey1, an effect that was abrogated by L-685,458. A 3 kb Hey1-promoter reporter construct was synergistically activated by the Notch 1 intracellular domain (Notch 1 ICD) and BMP4. The BMP4 mediator SMAD1 mimicked BMP activation of the Hey1 promoter. A synthetic Notch-responsive promoter containing no SMAD1 binding sites responded to SMAD1, indicating that DNA-binding activity of SMAD1 is not required for activation. Accordingly, Notch 1 ICD and SMAD1 interacted in binding experiments in vitro. Thus, the data presented here provide evidence for a direct interaction between the Notch and BMP signaling pathways, and indicate that Notch has a crucial role in the execution of certain aspects of BMP-mediated differentiation control.

BackgroundIt is usually assumed that musculoskeletal pain is associated with both the physical workload and the psychosocial work environment, as well as with personal and lifestyle factors. This study aims to ascertain the prevalence of musculoskeletal pain in women with varying or different occupational exposures, and to explore the associations between musculoskeletal pain and the occupational and personal factors.MethodsA questionnaire on physical, psychosocial and individual factors was answered by 1591 women in five occupational groups with contrasting occupational exposures (teachers, anaesthetic, theatre, and assistant nurses, and sonographers). The outcome measure was musculoskeletal pain (in a new model based on frequency and intensity of complaints the preceding year) from the neck, shoulders, hands, lower back and feet.ResultsNeck pain was equally frequent among teachers, assistant nurses and sonographers, and less frequent in anaesthetic and theatre nurses. The sonographers experienced the highest prevalence of shoulder pain, while the assistant nurses were the most affected in the wrists and hands, lower back, and feet.The teachers reported the highest scores in most of the psychosocial dimensions. The theatre nurses scored highest in strenuous work postures and movements (mechanical exposure index, MEI), and the assistant nurses in physical activity and lifting (physical exposure index, PHYI). Multivariable models in the total population showed that both the physical workload and the psychosocial work environment were associated with pain in all body regions, though different factors affected different regions. Pain in the neck, shoulders, hands and lower back was strongly associated with a high MEI and high job demands, while pain in the feet was associated with a high PHYI and a high BMI. A young age was associated with pain in the neck, and an older age was associated with pain in the hands and feet. Lack of time for personal recovery was associated with pain in the shoulders and lower back.ConclusionsThe occupational groups were affected differently and need different protective measures. For the teachers, the psychosocial work environment should be improved. The surgical staff and sonographers require measures to mitigate lifting and constrained postures.Electronic supplementary materialThe online version of this article (doi:10.1186/s12891-016-0883-4) contains supplementary material, which is available to authorized users.

Inhibition of Notch signaling by Numb is critical for many cell fate decisions. In this study, we demonstrate a more complex relationship between Notch and the two vertebrate Numb homologues Numb and Numblike. Although Numb and Numblike at low levels of Notch signaling negatively regulated Notch, high levels of Notch signaling conversely led to a reduction of Numb and Numblike protein levels in cultured cells and in the developing chick central nervous system. The Notch intracellular domain but not the canonical Notch downstream proteins Hes 1 and Hey 1 caused a reduction of Numb and Numblike. The Notch-mediated reduction of Numblike required the PEST domain in the Numblike protein and was blocked by the proteasome inhibitor MG132. Collectively, these observations reveal a reciprocal negative regulation between Notch and Numb/Numblike, which may be of relevance for stabilizing asymmetric cell fate switches and for tumor development.

There are several well-known risk factors for work-related musculoskeletal disorders (MSDs). Despite this knowledge, too many people still work in harmful conditions. The absence of occupational exposure limits (OELs) for physical workload impedes both supervision and preventive work. To prevent myalgia, tendon disorders, and nerve entrapments in the upper musculoskeletal system, we propose action levels concerning work postures, movement velocities and muscular loads recorded by wearable equipment. As an example, we propose that wrist velocity should not exceed 20°/s as a median over a working day. This has the potential to reduce the prevalence of carpal tunnel syndrome (CTS) in highly exposed male occupational groups by 93%. By reducing upper arm velocity in highly exposed female groups to the suggested action level 60°/s, the prevalence of pronounced neck/shoulder myalgia with clinical findings (tension neck syndrome) could be reduced by 22%. Furthermore, we propose several other action levels for the physical workload. Our ambition is to start a discussion concerning limits for physical workload, with the long-term goal that OELs shall be introduced in legislation. Obviously, the specific values of the proposed action levels can, and should, be discussed. We hope that quantitative measurements, combined with action levels, will become an integral part of systematic occupational health efforts, enabling reduction and prevention of work-related MSDs.