Dataset Information

Wnts Promote Synaptic Assembly Through T-Cell Specific Transcription Factors in Caenorhabditis elegans.

ABSTRACT: Synapses are specialized neuronal connections essential for neuronal function. Defects in synaptic assembly or maintenance usually lead to various neurological disorders. Synaptic assembly is regulated by secreted molecules such as Wnts. Wnts are a large family of conserved glycosylated signaling molecules involved in many aspects of neural development and maintenance. However, the molecular mechanisms by which Wnts regulate synaptic assembly remain elusive due to the large number of ligands/receptors, the diversity of signaling cascades and the complexity of the nervous system. In this study, through genetic manipulation, we uncover that C. elegans Wnt-2 (CWN-2) is required for synaptic development. The CWN-2 signal is required during both embryonic and postembryonic development, in the nervous system and intestine, for promoting synaptic assembly. Furthermore, we provide genetic evidence for CWN-2 promoting synaptogenesis through the Frizzled receptor (FZD) CFZ-2, the Dishevelled (DVL) DSH-2, the ?-catenin SYS-1 and the only T-cell specific transcription factor POP-1/TCF. Importantly, it is the first time to report the requirement of a TCF for presynaptic assembly. These findings expand our understanding of the synaptogenic mechanisms and may provide therapeutic insights into Wnt-related neurological disorders.

SUBMITTER: Shi Y

PROVIDER: S-EPMC6013564 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Wnts Promote Synaptic Assembly Through T-Cell Specific Transcription Factors in <i>Caenorhabditis elegans</i>.

Shi Yanjun Y Li Qian Q Shao Zhiyong Z

Frontiers in molecular neuroscience 20180615

Synapses are specialized neuronal connections essential for neuronal function. Defects in synaptic assembly or maintenance usually lead to various neurological disorders. Synaptic assembly is regulated by secreted molecules such as Wnts. Wnts are a large family of conserved glycosylated signaling molecules involved in many aspects of neural development and maintenance. However, the molecular mechanisms by which Wnts regulate synaptic assembly remain elusive due to the large number of ligands/rec ...[more]

PMID: 29962933

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Project description:During development, cell polarization is often coordinated to harmonize tissue patterning and morphogenesis. However, how extrinsic signals synchronize cell polarization is not understood. In Caenorhabditis elegans, most mitotic cells are polarized along the anterior-posterior axis and divide asymmetrically. Although this process is regulated by a Wnt-signaling pathway, Wnts functioning in cell polarity have been demonstrated in only a few cells. We analyzed how Wnts control cell polarity, using compound Wnt mutants, including animals with mutations in all five Wnt genes. We found that somatic gonadal precursor cells (SGPs) are properly polarized and oriented in quintuple Wnt mutants, suggesting Wnts are dispensable for the SGPs' polarity, which instead requires signals from the germ cells. Thus, signals from the germ cells organize the C. elegans somatic gonad. In contrast, in compound but not single Wnt mutants, most of the six seam cells, V1-V6 (which are epithelial stem cells), retain their polarization, but their polar orientation becomes random, indicating that it is redundantly regulated by multiple Wnt genes. In contrast, in animals in which the functions of three Wnt receptors (LIN-17, MOM-5, and CAM-1) are disrupted--the stem cells are not polarized and divide symmetrically--suggesting that the Wnt receptors are essential for generating polarity and that they function even in the absence of Wnts. All the seam cells except V5 were polarized properly by a single Wnt gene expressed at the cell's anterior or posterior. The ectopic expression of posteriorly expressed Wnts in an anterior region and vice versa rescued polarity defects in compound Wnt mutants, raising two possibilities: one, Wnts permissively control the orientation of polarity; or two, Wnt functions are instructive, but which orientation they specify is determined by the cells that express them. Our results provide a paradigm for understanding how cell polarity is coordinated by extrinsic signals.

Project description:Safeguarding the proteome is central to the health of the cell. In multi-cellular organisms, the composition of the proteome, and by extension, protein-folding requirements, varies between cells. In agreement, chaperone network composition differs between tissues. Here, we ask how chaperone expression is regulated in a cell type-specific manner and whether cellular differentiation affects chaperone expression. Our bioinformatics analyses show that the myogenic transcription factor HLH-1 (MyoD) can bind to the promoters of chaperone genes expressed or required for the folding of muscle proteins. To test this experimentally, we employed HLH-1 myogenic potential to genetically modulate cellular differentiation of Caenorhabditis elegans embryonic cells by ectopically expressing HLH-1 in all cells of the embryo and monitoring chaperone expression. We found that HLH-1-dependent myogenic conversion specifically induced the expression of putative HLH-1-regulated chaperones in differentiating muscle cells. Moreover, disrupting the putative HLH-1-binding sites on ubiquitously expressed daf-21(Hsp90) and muscle-enriched hsp-12.2(sHsp) promoters abolished their myogenic-dependent expression. Disrupting HLH-1 function in muscle cells reduced the expression of putative HLH-1-regulated chaperones and compromised muscle proteostasis during and after embryogenesis. In turn, we found that modulating the expression of muscle chaperones disrupted the folding and assembly of muscle proteins and thus, myogenesis. Moreover, muscle-specific over-expression of the DNAJB6 homolog DNJ-24, a limb-girdle muscular dystrophy-associated chaperone, disrupted the muscle chaperone network and exposed synthetic motility defects. We propose that cellular differentiation could establish a proteostasis network dedicated to the folding and maintenance of the muscle proteome. Such cell-specific proteostasis networks can explain the selective vulnerability that many diseases of protein misfolding exhibit even when the misfolded protein is ubiquitously expressed.

Project description:BackgroundTranscription regulatory networks are composed of interactions between transcription factors and their target genes. Whereas unicellular networks have been studied extensively, metazoan transcription regulatory networks remain largely unexplored. Caenorhabditis elegans provides a powerful model to study such metazoan networks because its genome is completely sequenced and many functional genomic tools are available. While C. elegans gene predictions have undergone continuous refinement, this is not true for the annotation of functional transcription factors. The comprehensive identification of transcription factors is essential for the systematic mapping of transcription regulatory networks because it enables the creation of physical transcription factor resources that can be used in assays to map interactions between transcription factors and their target genes.ResultsBy computational searches and extensive manual curation, we have identified a compendium of 934 transcription factor genes (referred to as wTF2.0). We find that manual curation drastically reduces the number of both false positive and false negative transcription factor predictions. We discuss how transcription factor splice variants and dimer formation may affect the total number of functional transcription factors. In contrast to mouse transcription factor genes, we find that C. elegans transcription factor genes do not undergo significantly more splicing than other genes. This difference may contribute to differences in organism complexity. We identify candidate redundant worm transcription factor genes and orthologous worm and human transcription factor pairs. Finally, we discuss how wTF2.0 can be used together with physical transcription factor clone resources to facilitate the systematic mapping of C. elegans transcription regulatory networks.ConclusionwTF2.0 provides a starting point to decipher the transcription regulatory networks that control metazoan development and function.

Dataset Information

Wnts Promote Synaptic Assembly Through T-Cell Specific Transcription Factors in Caenorhabditis elegans.

Publications

Wnts Promote Synaptic Assembly Through T-Cell Specific Transcription Factors in <i>Caenorhabditis elegans</i>.

Similar Datasets

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