Tissue polarity and PCP protein function: C. elegans as an emerging model

AbstractThe Microrchidia (MORC) family of ATPases are required for transposable element (TE) silencing and heterochromatin condensation in plants and animals, and C. elegans MORC-1 has been shown to topologically entrap and condense DNA. In Arabidopsis thaliana, mutation of MORCs has been shown to reactivate silent methylated genes and transposons and to decondense heterochromatic chromocenters, despite only minor changes in the maintenance of DNA methylation. Here we provide the first evidence localizing Arabidopsis MORC proteins to specific regions of chromatin and find that MORC4 and MORC7 are closely co-localized with sites of RNA-directed DNA methylation (RdDM). We further show that MORC7, when tethered to DNA by an artificial zinc finger, can facilitate the establishment of RdDM. Finally, we show that MORCs are required for the efficient RdDM mediated establishment of DNA methylation and silencing of a newly integrated FWA transgene, even though morc mutations have no effect on the maintenance of preexisting methylation at the endogenous FWA gene. We propose that MORCs function as a molecular tether in RdDM complexes to reinforce RdDM activity for methylation establishment. These findings have implications for MORC protein function in a variety of other eukaryotic organisms.

Download Full-text

Latrophilin Signaling Links Anterior-Posterior Tissue Polarity and Oriented Cell Divisions in the C. elegans Embryo

Developmental Cell ◽

10.1016/j.devcel.2009.08.008 ◽

2009 ◽

Vol 17 (4) ◽

pp. 494-504 ◽

Cited By ~ 90

Author(s):

Tobias Langenhan ◽

Simone Prömel ◽

Lamia Mestek ◽

Behrooz Esmaeili ◽

Helen Waller-Evans ◽

...

Keyword(s):

Tissue Polarity ◽

C Elegans ◽

Cell Divisions ◽

Anterior Posterior

Download Full-text

C. elegans PVD Neurons: A Platform for Functionally Validating and Characterizing Neuropsychiatric Risk Genes

10.1101/053900 ◽

2016 ◽

Author(s):

Cristina Aguirre-Chen ◽

Nuri Kim ◽

Olivia Mendivil Ramos ◽

Melissa Kramer ◽

W. Richard McCombie ◽

...

Keyword(s):

Protein Function ◽

Molecular Mechanisms ◽

Neuronal Development ◽

De Novo ◽

Genetic Interaction ◽

Cost Effective ◽

Chromatin Remodelers ◽

C Elegans ◽

Effective Manner

AbstractOne of the primary challenges in the field of psychiatric genetics is the lack of an in vivo model system in which to functionally validate candidate neuropsychiatric risk genes (NRGs) in a rapid and cost-effective manner1−3. To overcome this obstacle, we performed a candidate-based RNAi screen in which C. elegans orthologs of human NRGs were assayed for dendritic arborization and cell specification defects using C. elegans PVD neurons. Of 66 NRGs, identified via exome sequencing of autism (ASD)4 or schizophrenia (SCZ)5−9 probands and whose mutations are de novo and predicted to result in a complete or partial loss of protein function, the C. elegans orthologs of 7 NRGs were found to be required for proper neuronal development and represent a variety of functional classes, including transcriptional regulators and chromatin remodelers, molecular chaperones, and cytoskeleton-related proteins. Notably, the positive hit rate, when selectively assaying C. elegans orthologs of ASD and SCZ NRGs, is enriched >14-fold as compared to unbiased RNAi screening10. Furthermore, we find that RNAi phenotypes associated with the depletion of NRG orthologs is recapitulated in genetic mutant animals, and, via genetic interaction studies, we show that the NRG ortholog of ANK2, unc-44, is required for SAX-7/MNR-1/DMA-1 signaling. Collectively, our studies demonstrate that C. elegans PVD neurons are a tractable model in which to discover and dissect the fundamental molecular mechanisms underlying neuropsychiatric disease pathogenesis.

Download Full-text

egl-27 generates anteroposterior patterns of cell fusion in C. elegans by regulating Hox gene expression and Hox protein function

Development ◽

10.1242/dev.126.15.3303 ◽

1999 ◽

Vol 126 (15) ◽

pp. 3303-3312 ◽

Cited By ~ 1

Author(s):

Q. Ch'ng ◽

C. Kenyon

Keyword(s):

Gene Expression ◽

Cell Fusion ◽

Protein Function ◽

Hox Genes ◽

Positional Information ◽

Cell Fates ◽

Hox Proteins ◽

Hox Gene ◽

C Elegans ◽

Hox Protein

Hox genes pattern the fates of the ventral ectodermal Pn.p cells that lie along the anteroposterior (A/P) body axis of C. elegans. In these cells, the Hox genes are expressed in sequential overlapping domains where they control the ability of each Pn.p cell to fuse with the surrounding syncytial epidermis. The activities of Hox proteins are sex-specific in this tissue, resulting in sex-specific patterns of cell fusion: in hermaphrodites, the mid-body cells remain unfused, whereas in males, alternating domains of syncytial and unfused cells develop. We have found that the gene egl-27, which encodes a C. elegans homologue of a chromatin regulatory factor, specifies these patterns by regulating both Hox gene expression and Hox protein function. In egl-27 mutants, the expression domains of Hox genes in these cells are shifted posteriorly, suggesting that egl-27 influences A/P positional information. In addition, egl-27 controls Hox protein function in the Pn.p cells in two ways: in hermaphrodites it inhibits MAB-5 activity, whereas in males it permits a combinatorial interaction between LIN-39 and MAB-5. Thus, by selectively modifying the activities of Hox proteins, egl-27 elaborates a simple Hox expression pattern into complex patterns of cell fates. Taken together, these results implicate egl-27 in the diversification of cell fates along the A/P axis and suggest that chromatin reorganization is necessary for controlling Hox gene expression and Hox protein function.

Download Full-text

Functional comparison of the nematode Hox gene lin-39 in C. elegans and P. pacificus reveals evolutionary conservation of protein function despite divergence of primary sequences

Genes & Development ◽

10.1101/gad.200601 ◽

2001 ◽

Vol 15 (16) ◽

pp. 2161-2172 ◽

Cited By ~ 10

Author(s):

K. Grandien

Keyword(s):

Protein Function ◽

Evolutionary Conservation ◽

Hox Gene ◽

C Elegans

Download Full-text

UBC-9 Acts in GABA Neurons to Control Neuromuscular Signaling in C. elegans

Neuroscience Insights ◽

10.1177/2633105520962792 ◽

2020 ◽

Vol 15 ◽

pp. 263310552096279

Author(s):

Victoria A Kreyden ◽

Elly B Mawi ◽

Kristen M Rush ◽

Jennifer R Kowalski

Keyword(s):

Nervous System ◽

Synaptic Vesicle ◽

Motor Neurons ◽

Protein Function ◽

Cholinergic Neurons ◽

Synaptic Proteins ◽

Inhibitory Synapses ◽

C Elegans ◽

Associated Proteins ◽

Inhibitory Signaling

Regulation of excitatory to inhibitory signaling balance is essential to nervous system health and is maintained by numerous enzyme systems that modulate the activity, localization, and abundance of synaptic proteins. SUMOylation is a key post-translational regulator of protein function in diverse cells, including neurons. There, its role in regulating synaptic transmission through pre- and postsynaptic effects has been shown primarily at glutamatergic central nervous system synapses, where the sole SUMO-conjugating enzyme Ubc9 is a critical player. However, whether Ubc9 functions globally at other synapses, including inhibitory synapses, has not been explored. Here, we investigated the role of UBC-9 and the SUMOylation pathway in controlling the balance of excitatory cholinergic and inhibitory GABAergic signaling required for muscle contraction in Caenorhabditis elegans. We found inhibition or overexpression of UBC-9 in neurons modestly increased muscle excitation. Similar and even stronger phenotypes were seen with UBC-9 overexpression specifically in GABAergic neurons, but not in cholinergic neurons. These effects correlated with accumulation of synaptic vesicle-associated proteins at GABAergic presynapses, where UBC-9 and the C. elegans SUMO ortholog SMO-1 localized, and with defects in GABA-dependent behaviors. Experiments involving expression of catalytically inactive UBC-9 [UBC-9(C93S)], as well as co-expression of UBC-9 and SMO-1, suggested wild type UBC-9 overexpressed alone may act via substrate sequestration in the absence of sufficient free SUMO, underscoring the importance of tightly regulated SUMO enzyme function. Similar effects on muscle excitation, GABAergic signaling, and synaptic vesicle localization occurred with overexpression of the SUMO activating enzyme subunit AOS-1. Together, these data support a model in which UBC-9 and the SUMOylation system act at presynaptic sites in inhibitory motor neurons to control synaptic signaling balance in C. elegans. Future studies will be important to define UBC-9 targets at this synapse, as well as mechanisms by which UBC-9 and the SUMO pathway are regulated.

Download Full-text