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APOBEC2, a selective inhibitor of TGF? signaling, regulates left-right axis specification during early embryogenesis.

ABSTRACT: The specification of left-right asymmetry is an evolutionarily conserved developmental process in vertebrates. The interplay between two TGF? ligands, Derrière/GDF1 and Xnr1/Nodal, together with inhibitors such as Lefty and Coco/Cerl2, have been shown to provide the signals that lead to the establishment of laterality. However, molecular events leading to and following these signals remain mostly unknown. We find that APOBEC2, a member of the cytidine deaminase family of DNA/RNA editing enzymes, is induced by TGF? signaling, and that its activity is necessary to specify the left-right axis in Xenopus and zebrafish embryos. Surprisingly, we find that APOBEC2 selectively inhibits Derrière, but not Xnr1, signaling. The inhibitory effect is conserved, as APOBEC2 blocks TGF? signaling, and promotes muscle differentiation, in a mammalian myoblastic cell line. This demonstrates for the first time that a putative RNA/DNA editing enzyme regulates TGF? signaling and plays a major role in development.

SUBMITTER: Vonica A

PROVIDER: S-EPMC3038383 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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APOBEC2, a selective inhibitor of TGFβ signaling, regulates left-right axis specification during early embryogenesis.

Vonica Alin A Rosa Alessandro A Arduini Brigitte L BL Brivanlou Ali H AH

Developmental biology 20100927 1

The specification of left-right asymmetry is an evolutionarily conserved developmental process in vertebrates. The interplay between two TGFβ ligands, Derrière/GDF1 and Xnr1/Nodal, together with inhibitors such as Lefty and Coco/Cerl2, have been shown to provide the signals that lead to the establishment of laterality. However, molecular events leading to and following these signals remain mostly unknown. We find that APOBEC2, a member of the cytidine deaminase family of DNA/RNA editing enzymes, ...[more]

PMID: 20880495

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Project description:BackgroundLeft-right asymmetries are a common feature of metazoans and can be found in a number of organs including the nervous system. These asymmetries are particularly pronounced in the simple central nervous system (CNS) of the swimming tadpole larva of the tunicate Ciona, which displays a chordate ground plan. While common pathway elements for specifying the left/right axis are found among chordates, particularly a requirement for Nodal signaling, Ciona differs temporally from its vertebrate cousins by specifying its axis at the neurula stage, rather than at gastrula. Additionally, Ciona and other ascidians require an intact chorionic membrane for proper left-right specification. Whether such differences underlie distinct specification mechanisms between tunicates and vertebrates will require broad understanding of their influence on CNS formation. Here, we explore the consequences of disrupting left-right axis specification on Ciona larval CNS cellular anatomy, gene expression, synaptic connectivity, and behavior.ResultsWe show that left-right asymmetry disruptions caused by removal of the chorion (dechorionation) are highly variable and present throughout the Ciona larval nervous system. While previous studies have documented disruptions to the conspicuously asymmetric sensory systems in the anterior brain vesicle, we document asymmetries in seemingly symmetric structures such as the posterior brain vesicle and motor ganglion. Moreover, defects caused by dechorionation include misplaced or absent neuron classes, loss of asymmetric gene expression, aberrant synaptic projections, and abnormal behaviors. In the motor ganglion, a brain structure that has been equated with the vertebrate hindbrain, we find that despite the apparent left-right symmetric distribution of interneurons and motor neurons, AMPA receptors are expressed exclusively on the left side, which equates with asymmetric swimming behaviors. We also find that within a population of dechorionated larvae, there is a small percentage with apparently normal left-right specification and approximately equal population with inverted (mirror-image) asymmetry. We present a method based on a behavioral assay for isolating these larvae. When these two classes of larvae (normal and inverted) are assessed in a light dimming assay, they display mirror-image behaviors, with normal larvae responding with counterclockwise swims, while inverted larvae respond with clockwise swims.ConclusionsOur findings highlight the importance of left-right specification pathways not only for proper CNS anatomy, but also for correct synaptic connectivity and behavior.

Project description:Anatomically and functionally defined neuron types are sometimes further classified into individual subtypes based on unique functional or molecular properties. To better understand how developmental programs controlling neuron type specification are mechanistically linked to programs controlling neuronal subtype specification, we have analyzed a neuronal subtype specification program that occurs across the left/right axis in the nervous system of the nematode C. elegans. A terminal selector transcription factor, CHE-1, is required for the specification of the ASE neuron class, and a gene regulatory feedback loop of transcription factors and miRNAs is required to diversify the two ASE neurons into an asymmetric left and right subtype (ASEL and ASER). However, the link between the CHE-1-dependent ASE neuron class specification and the ensuing left-right subtype specification program is poorly understood. We show here that CHE-1 has genetically separable functions in controlling bilaterally symmetric ASE neuron class specification and the ensuing left-right subtype specification program. Both neuron class specification and asymmetric subclass specification depend on CHE-1-binding sites (;ASE motifs') in symmetrically and asymmetrically expressed target genes, but in the case of asymmetrically expressed target genes, the activity of the ASE motif is modulated through a diverse set of additional cis-regulatory elements. Depending on the target gene, these cis-regulatory elements either promote or inhibit the activity of CHE-1. The activity of these L/R asymmetric cis-regulatory elements is indirectly controlled by che-1 itself, revealing a feed-forward loop configuration in which che-1 restricts its own activity. Relative binding affinity of CHE-1 to ASE motifs also depends on whether a gene is expressed bilaterally or in a left/right asymmetric manner. Our analysis provides insights into the molecular mechanisms of neuronal subtype specification, demonstrating that the activity of a neuron type-specific selector gene is modulated by a variety of distinct means to diversify individual neuron classes into specific subclasses. It also suggests that feed-forward loop motifs may be a prominent feature of neuronal diversification events.

Project description:The relative contributions of the left and right hemispheres to the processing of metaphoric language remains unresolved. Neuropsychological studies of brain-injured patients have motivated the hypothesis that the right hemisphere plays a critical role in understanding metaphors. However, the data are inconsistent and the hypothesis is not well-supported by neuroimaging research. To address this ambiguity about the right hemisphere's role, we administered a metaphor sentence comprehension task to 20 left-hemisphere injured patients, 20 right hemisphere injured patients, and 20 healthy controls. Stimuli consisted of metaphors of three different types: predicate metaphors based on action verbs, nominal metaphors based on event nouns, and nominal metaphors based on entity nouns. For each metaphor (n = 60), a closely matched literal sentence with the same source term was also generated. Each sentence was followed by four adjective-noun answer choices (target + three foil types) and participants were instructed to select the phrase that best matched the meaning of the sentence. As a group, both left and right hemisphere patients performed worse on metaphoric than literal sentences, and the degree of this difficulty varied for the different types of metaphor - but there was no difference between the two patient groups. Tests for literal-metaphor dissociations at the level of single cases revealed two types of impairments: general comprehension deficits affecting metaphors and literal sentences equally, and selective metaphor impairments that were specific to different types of metaphor. All cases with selective metaphor deficits had injury to the left hemisphere, and no known comprehension difficulties with literal language. Our results argue against the hypothesis of a specific or necessary contribution of the right hemisphere for understanding metaphoric language. Further, they reveal deficits in metaphoric language comprehension not captured by traditional language assessments, suggesting overlooked communication difficulties in left hemisphere patients.

Dataset Information

APOBEC2, a selective inhibitor of TGF? signaling, regulates left-right axis specification during early embryogenesis.

Publications

APOBEC2, a selective inhibitor of TGFβ signaling, regulates left-right axis specification during early embryogenesis.

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