Caenorhabditis elegans Muscleblind homolog mbl-1 functions in neurons to regulate synapse formation

Spilker, Kerri; Wang, George J.; Tugizova, Madina; Shen, Kang

doi:10.1186/1749-8104-7-7

Cited by 34 publications

(43 citation statements)

References 39 publications

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“…We then examined the development of ventral cholinergic synapses using a chromosomally integrated transgene that expresses GFP::RAB-3 from the cholinergic neuronspecific promoter unc-4 (Spilker et al 2012). We found that cholinergic synapses were present dorsally throughout development.…”

Section: Resultsmentioning

confidence: 99%

An Evolutionarily Conserved Switch in Response to GABA Affects Development and Behavior of the Locomotor Circuit of Caenorhabditis elegans

Han¹,

Bellemer

Koelle

2015

Genetics

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The neurotransmitter gamma-aminobutyric acid (GABA) is depolarizing in the developing vertebrate brain, but in older animals switches to hyperpolarizing and becomes the major inhibitory neurotransmitter in adults. We discovered a similar developmental switch in GABA response in Caenorhabditis elegans and have genetically analyzed its mechanism and function in a well-defined circuit. Worm GABA neurons innervate body wall muscles to control locomotion. Activation of GABA A receptors with their agonist muscimol in newly hatched first larval (L1) stage animals excites muscle contraction and thus is depolarizing. At the mid-L1 stage, as the GABAergic neurons rewire onto their mature muscle targets, muscimol shifts to relaxing muscles and thus has switched to hyperpolarizing. This muscimol response switch depends on chloride transporters in the muscles analogous to those that control GABA response in mammalian neurons: the chloride accumulator sodium-potassium-chloride-cotransporter-1 (NKCC-1) is required for the early depolarizing muscimol response, while the two chloride extruders potassium-chloride-cotransporter-2 (KCC-2) and anion-bicarbonate-transporter-1 (ABTS-1) are required for the later hyperpolarizing response. Using mutations that disrupt GABA signaling, we found that neural circuit development still proceeds to completion but with an 6-hr delay. Using optogenetic activation of GABAergic neurons, we found that endogenous GABA A signaling in early L1 animals, although presumably depolarizing, does not cause an excitatory response. Thus a developmental depolarizing-tohyperpolarizing shift is an ancient conserved feature of GABA signaling, but existing theories for why this shift occurs appear inadequate to explain its function upon rigorous genetic analysis of a well-defined neural circuit.

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Section: Resultsmentioning

confidence: 99%

An Evolutionarily Conserved Switch in Response to GABA Affects Development and Behavior of the Locomotor Circuit of Caenorhabditis elegans

Han¹,

Bellemer

Koelle

2015

Genetics

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“…Indeed, NMJ degeneration has been observed in diaphragm muscles in mouse models of DM (Panaite et al, 2008). Additionally, motor neurons derived from human DM ES cells fail to form mature neuromuscular connections with normal muscle (Marteyn et al, 2011), and worms deficient in neuronal muscleblind expression fail to form distal NMJs, implicating pre-synaptic dysregulation (Spilker et al, 2012). Secretion of proteins with important functions in muscle may also be affected in DM.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome-wide Regulation of Pre-mRNA Splicing and mRNA Localization by Muscleblind Proteins

Wang

Cody

Jog

et al. 2012

Cell

449

558

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Summary The Muscleblind-like (Mbnl) family of RNA binding proteins plays important roles in muscle and eye development and in Myotonic Dystrophy (DM), where expanded CUG or CCUG repeats functionally deplete Mbnl proteins. We identified transcriptome-wide functional and biophysical targets of Mbnl proteins in brain, heart, muscle, and myoblasts using RNA-Seq and CLIP-Seq approaches. This analysis identified several hundred splicing events whose regulation depended on Mbnl function, in a pattern indicating functional interchangeability between Mbnl1 and Mbnl2. A nucleotide resolution RNA map associated repression or activation of exon splicing with Mbnl binding near either 3' splice site or near the downstream 5' splice site, respectively. Transcriptomic analysis of sub-cellular compartments uncovered a global role for Mbnls in regulating localization of mRNAs in both mouse and Drosophila cells, and Mbnl-dependent translation and protein secretion was observed for a subset of mRNAs with Mbnl-dependent localization. These findings hold several new implications for DM pathogenesis.

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“…Previous studies have shown both Reelin and CLASP2 play direct roles in modulating neuronal polarization through the regulation of both Golgi shape and deployment into the leading process (Matsuki et al 2010; O’Dell et al, 2012; Beffert et al, 2012). In addition, CLASP-dependent nucleation of microtubules at the Golgi is required for directional cargo trafficking (Miller et al, 2009; Efimov et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

CLASP2 Links Reelin to the Cytoskeleton during Neocortical Development

Dillon

Tyler

Omuro

et al. 2017

Neuron

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SUMMARY The Reelin signaling pathway plays a crucial role in regulating neocortical development. However, little is known about how Reelin controls the cytoskeleton during neuronal migration. Here, we identify CLASP2 as a key cytoskeletal effector in the Reelin signaling pathway. We demonstrate that CLASP2 has distinct roles during neocortical development regulating neuron production and controlling neuron migration, polarity, and morphogenesis. We found down-regulation of CLASP2 in migrating neurons leads to mislocalized cells in deeper cortical layers, abnormal positioning of the centrosome-Golgi complex, and aberrant length/orientation of the leading process. We discovered Reelin regulates several phosphorylation sites within the positively-charged serine/arginine rich region that constitute consensus GSK3β phosphorylation motifs of CLASP2. Furthermore, phosphorylation of CLASP2 regulates its interaction with the Reelin adaptor Dab1 and this association is required for CLASP2 effects on neurite extension and motility. Together, our data reveal CLASP2 is an essential Reelin effector orchestrating cytoskeleton dynamics during brain development.

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Caenorhabditis elegans Muscleblind homolog mbl-1 functions in neurons to regulate synapse formation

Cited by 34 publications

References 39 publications

An Evolutionarily Conserved Switch in Response to GABA Affects Development and Behavior of the Locomotor Circuit of Caenorhabditis elegans

An Evolutionarily Conserved Switch in Response to GABA Affects Development and Behavior of the Locomotor Circuit of Caenorhabditis elegans

Transcriptome-wide Regulation of Pre-mRNA Splicing and mRNA Localization by Muscleblind Proteins

CLASP2 Links Reelin to the Cytoskeleton during Neocortical Development

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