ABSTRACT
Nephronophthisis (NPH), an autosomal recessive ciliopathy, results from mutations in more than 20 different genes (NPHPs). These gene products form protein complexes that regulate trafficking within the cilium, a microtubular structure that plays a crucial role in developmental processes. Several NPHPs, including NPHP2/Inversin, have been linked to extraciliary functions. In addition to defining a specific segment of primary cilia (Inversin compartment), NPHP2 participates in planar cell polarity (PCP) signaling along with Dishevelled and Vangl family members. We used the mutant zebrafish line invssa36157, containing a stop codon at amino acid 314, to characterize tissue-specific functions of zebrafish Nphp2. The invssa36157 line exhibits mild ciliopathy phenotypes and increased glomerular and cloaca cyst formation. These mutants showed enhanced susceptibility to the simultaneous depletion of the nphp1/nphp2/nphp8 module, known to be involved in the cytoskeletal organization of epithelial cells. Notably, simultaneous depletion of zebrafish nphp1 and vangl2 led to a pronounced increase in cloaca malformations in the invssa36157 mutant embryos. Time-lapse imaging showed that the pronephric cells correctly migrated towards the ectodermal cells in these embryos, but failed to form the cloaca opening. Despite these abnormal developments, cellular fate does not seem to be affected in nphp1 and vangl2 MO-depleted invssa36157 mutants, as shown by in situ hybridizations for markers of pronephros and ectodermal cell development. However, significantly reduced apoptotic activity was observed in this double knockdown model, signifying the role of apoptosis in cloacal morphogenesis. Our findings underscore the critical interplay of nphp1, nphp2/Inversin, and vangl2 in orchestrating normal cloaca formation in zebrafish, shedding light on the complex molecular mechanisms underlying ciliopathy-associated phenotypes.
Subject(s)
Cloaca , Zebrafish , Animals , Zebrafish/genetics , Zebrafish/metabolism , Cloaca/metabolism , Cell Polarity , Membrane Proteins/genetics , Zebrafish Proteins/genetics , Zebrafish Proteins/metabolismABSTRACT
BACKGROUND: Childhood and adolescent overweight can still be seen as a global public health problem. Based on our socioeconomic understanding, overweight is the result of a complex interplay of a diverse array of factors acting on different levels. Hence, in addition to individual level determinants overweight prevention should also address environmental related factors as part of a holistic and integrated setting approach. OBJECTIVE: This paper aims to discuss the setting approach with regard to overweight prevention in childhood and adolescence. In addition to a summary of environmental factors and their empirical influence on the determinants of overweight, theoretical approaches and planning models of settings-based overweight prevention are discussed. RESULTS: While settings can be characterized as specific social-spatial subsystems (e. g. kindergarten, schools), living environments relate to complex subject-oriented environments that may include various subsystems. Direct social contexts, educational contexts and community contexts as relevant systems for young people contain different evidence-based influences that need to be taken into account in settings based overweight prevention. To support a theory-driven intervention, numerous planning models exist, which are presented here. DISCUSSION: Given the strengthening of environments for health within the prevention law, the underlying settings approach also needs further development with regard to overweigth prevention. This includes the improvement of the theoretical foundation by aligning intervention practice of planning models, which also has a positive influence on the ability to measure its success.
