Wnt/Frizzled Signaling Requires dPRR, the Drosophila Homolog of the Prorenin Receptor

SummaryWnt/Wg signaling pathways are of key importance during development and disease [1–4]. Canonical and noncanonical Wnt/Frizzled (Fz) pathways share a limited number of signaling components that are part of the membrane proximal signaling complex. In Drosophila, Fz [5–7] and Dishevelled (Dsh) [8, 9] are the only two components known to be involved in both Wnt/β-catenin and planar cell polarity (PCP) signaling. PCP signaling is required for the planar polarization of epithelial cells [10, 11], which occurs, for instance, during hair orientation and gastrulation in vertebrates [12]. Both pathways have been studied intensively in the past years. However, it still remains unresolved whether additional components are required at the receptor complex. Here we identify the Drosophila homolog of the mammalian prorenin receptor (dPRR) as a conserved modulator of canonical Wnt/β-cat and Fz/PCP signaling. We show that dPRR depletion affects Wg target genes in cultured cells and in vivo. PRR is required for epithelial planar polarity in Drosophila and for convergent extension movements in Xenopus gastrulae. Furthermore, dPRR binds to Fz and Fz2 receptors. In summary, our data suggest that dPRR has an evolutionarily conserved role at the receptor level for activation of canonical and noncanonical Wnt/Fz signaling pathways

Secreted Signaling Molecules at the Neuromuscular Junction in Physiology and Pathology

Signal transduction at the neuromuscular junction (NMJ) is affected in many human diseases, including congenital myasthenic syndromes (CMS), myasthenia gravis, Lambert–Eaton myasthenic syndrome, Isaacs’ syndrome, Schwartz–Jampel syndrome, Fukuyama-type congenital muscular dystrophy, amyotrophic lateral sclerosis, and sarcopenia. The NMJ is a prototypic cholinergic synapse between the motor neuron and the skeletal muscle. Synaptogenesis of the NMJ has been extensively studied, which has also been extrapolated to further understand synapse formation in the central nervous system. Studies of genetically engineered mice have disclosed crucial roles of secreted molecules in the development and maintenance of the NMJ. In this review, we focus on the secreted signaling molecules which regulate the clustering of acetylcholine receptors (AChRs) at the NMJ. We first discuss the signaling pathway comprised of neural agrin and its receptors, low-density lipoprotein receptor-related protein 4 (Lrp4) and muscle-specific receptor tyrosine kinase (MuSK). This pathway drives the clustering of acetylcholine receptors (AChRs) to ensure efficient signal transduction at the NMJ. We also discuss three secreted molecules (Rspo2, Fgf18, and connective tissue growth factor (Ctgf)) that we recently identified in the Wnt/β-catenin and fibroblast growth factors (FGF) signaling pathways. The three secreted molecules facilitate the clustering of AChRs by enhancing the agrin-Lrp4-MuSK signaling pathway

Secreted Signaling Molecules at the Neuromuscular Junction in Physiology and Pathology

Signal transduction at the neuromuscular junction (NMJ) is affected in many human diseases, including congenital myasthenic syndromes (CMS), myasthenia gravis, Lambert–Eaton myasthenic syndrome, Isaacs’ syndrome, Schwartz–Jampel syndrome, Fukuyama-type congenital muscular dystrophy, amyotrophic lateral sclerosis, and sarcopenia. The NMJ is a prototypic cholinergic synapse between the motor neuron and the skeletal muscle. Synaptogenesis of the NMJ has been extensively studied, which has also been extrapolated to further understand synapse formation in the central nervous system. Studies of genetically engineered mice have disclosed crucial roles of secreted molecules in the development and maintenance of the NMJ. In this review, we focus on the secreted signaling molecules which regulate the clustering of acetylcholine receptors (AChRs) at the NMJ. We first discuss the signaling pathway comprised of neural agrin and its receptors, low-density lipoprotein receptor-related protein 4 (Lrp4) and muscle-specific receptor tyrosine kinase (MuSK). This pathway drives the clustering of acetylcholine receptors (AChRs) to ensure efficient signal transduction at the NMJ. We also discuss three secreted molecules (Rspo2, Fgf18, and connective tissue growth factor (Ctgf)) that we recently identified in the Wnt/β-catenin and fibroblast growth factors (FGF) signaling pathways. The three secreted molecules facilitate the clustering of AChRs by enhancing the agrin-Lrp4-MuSK signaling pathway

Restriction mechanism of bone morphogenetic protein in the early development of Xenopus Laevis

During early development, cells receive positional information from neighboring cells that direct how they should differentiate to form tissue patterns from initially uniform germ layers.Ligands of the transforming growth factor (TGF-β) superfamily are known to participate in this pattern formation. In particular, activin has been shown to act as a long-range signal to establish a concentration gradient in X enopus ectoderm.In contrast, the action of BMP-2 and BMP-4, both of which also belong to this superfamily, appears to be restricted to the ventral ectoderm where they induce the epidermal fate in a tightly localized manner.This raises a question as to how the action of BMP is tightly restricted to within and around the cells that produce it.To investigate this question, I noticed that some of the BMP subfamily ligands contain a unique core of basic amino acids in their N-terminus.Then cDNA encoding BMP-4 variants, lacking basic amino acids core in their N-terminal region, were constructed.To analyze their action ranges in Xenopus embryo, the experiments using presumptive ectoderm and whole embryo were preformed.Results are, first, that a basic core of only three amino acids in the N-terminal region of BMP-4 is required not for its biological activity but for its restriction to the non-neural ectoderm and to the ventral tissue. Second, I demonstrated that heparan sulfate proteoglycans (HSPGs) bind to this basic core and WTBMP-4 could act as long-range siganl molecules where HSPGs are absent in vivo.These observations suggest that the basic amino acids in the N-terminal region of BMP-4 and particularly the basic core play an essential role in conferring to BMP-4 a short-range action in vivo.And I demonstrated that at least one of the molecules trapping WTBMP-4 on the surface of animal cap cells is HSPGs in vivo.The present work first identifies the critical domain of BMP for the restriction of its diffusion through the interaction with extracellular environments in vivo

Role of the TAK1-NLK-STAT3 pathway in TGF-β-mediated mesoderm induction

Transforming growth factor (TGF)-β-activated kinase 1 (TAK1) and Nemo-like kinase (NLK) function in Xenopus, Drosophila, and Caenorhabditis elegans development. Here we report that serine phosphorylation of STAT3 induced by TAK1-NLK cascade is essential for TGF-β-mediated mesoderm induction in Xenopus embryo. Depletion of TAK1, NLK, or STAT3 blocks TGF-β-mediated mesoderm induction. Coexpression of NLK and STAT3 induces mesoderm by a mechanism that requires serine phosphorylation of STAT3. Activin activates NLK, which in turn directly phosphorylates STAT3. Moreover, depletion of either TAK1 or NLK inhibits endogenous serine phosphorylation of STAT3. These results provide the first evidence that TAK1-NLK-STAT3 cascade participates in TGF-β-mediated mesoderm induction