Loss of motoneuron-specific microRNA-218 causes systemic neuromuscular failure

Amin, Neal D.; Bai, Ge; Klug, Jason R.; Bonanomi, Dario; Pankratz, Matthew; Gifford, Wesley D.; Hinckley, Christopher A.; Sternfeld, Matthew J; Driscoll, Shawn P.; Dominguez, Bertha; Lee, Kuo‐Fen; Jin, Xin; Pfaff, Samuel L.

doi:10.1126/science.aad2509

Cited by 130 publications

(130 citation statements)

References 30 publications

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“…Interestingly, ChIP-seq data for LHX3 binding loci also showed the highest peak at the same genomic region (Fig. 5A)323334. This indicates that ISL1 and LHX3 together may drive Slit2 transcription in SM neurons, probably by forming the ISL1 and LHX3 hexameric complex235.…”

Section: Resultsmentioning

confidence: 83%

ISL1-based LIM complexes control Slit2 transcription in developing cranial motor neurons

Kim

et al. 2016

Sci Rep

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LIM-homeodomain (HD) transcription factors form a multimeric complex and assign neuronal subtype identities, as demonstrated by the hexameric ISL1-LHX3 complex which gives rise to somatic motor (SM) neurons. However, the roles of combinatorial LIM code in motor neuron diversification and their subsequent differentiation is much less well understood. In the present study, we demonstrate that the ISL1 controls postmitotic cranial branchiomotor (BM) neurons including the positioning of the cell bodies and peripheral axon pathfinding. Unlike SM neurons, which transform into interneurons, BM neurons are normal in number and in marker expression in Isl1 mutant mice. Nevertheless, the movement of trigeminal and facial BM somata is stalled, and their peripheral axons are fewer or misrouted, with ectopic branches. Among genes whose expression level changes in previous ChIP-seq and microarray analyses in Isl1-deficient cell lines, we found that Slit2 transcript was almost absent from BM neurons of Isl1 mutants. Both ISL1-LHX3 and ISL1-LHX4 bound to the Slit2 enhancer and drove endogenous Slit2 expression in SM and BM neurons. Our findings suggest that combinations of ISL1 and LHX factors establish cell-type specificity and functional diversity in terms of motor neuron identities and/or axon development.

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Section: Resultsmentioning

confidence: 83%

ISL1-based LIM complexes control Slit2 transcription in developing cranial motor neurons

Kim

et al. 2016

Sci Rep

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“…Furthermore, although cell culture models have provided much insight into the role of miRNAs in neural development, animal models that examine miRNA function at the organismic level are still scarce. Nevertheless, first results from miRNA KO models are highly encouraging and suggest that the loss of specific miRNAs can have rather profound consequences for the development of neural circuits and animal behavior (Amin et al, 2015;Tan et al, 2013). Applying CRISPR-Cas technology to analyze miRNA function in the brain will no doubt accelerate efforts to investigate the physiological function of specific miRNA-target interactions.…”

Section: Discussionmentioning

confidence: 99%

MicroRNAs in neural development: from master regulators to fine-tuners

2017

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The proper formation and function of neuronal networks is required for cognition and behavior. Indeed, pathophysiological states that disrupt neuronal networks can lead to neurodevelopmental disorders such as autism, schizophrenia or intellectual disability. It is wellestablished that transcriptional programs play major roles in neural circuit development. However, in recent years, post-transcriptional control of gene expression has emerged as an additional, and probably equally important, regulatory layer. In particular, it has been shown that microRNAs (miRNAs), an abundant class of small regulatory RNAs, can regulate neuronal circuit development, maturation and function by controlling, for example, local mRNA translation. It is also becoming clear that miRNAs are frequently dysregulated in neurodevelopmental disorders, suggesting a role for miRNAs in the etiology and/or maintenance of neurological disease states. Here, we provide an overview of the most prominent regulatory miRNAs that control neural development, highlighting how they act as 'master regulators' or 'fine-tuners' of gene expression, depending on context, to influence processes such as cell fate determination, cell migration, neuronal polarization and synapse formation.

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“…However, similar to ChAT, its expression is detectable only in more mature MNs. Non-traditional molecular markers such as micro-RNAs (miRs) have promising utility for accurate MN identification in vitro , with miR-218 being recently identified to be the most MN-specific to date 54 .…”

Section: General and Sub-type Specific Markers Of Hpsc-lmnsmentioning

confidence: 99%

Modeling ALS with motor neurons derived from human induced pluripotent stem cells

et al. 2016

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Directing the differentiation of induced pluripotent stem cells into motor neurons has allowed investigators to develop novel models of ALS. However, techniques vary between laboratories and the cells do not appear to mature into fully functional adult motor neurons. Here we discuss common developmental principles of both lower and upper motor neuron development that have led to specific derivation techniques. We then suggest how these motor neurons may be matured further either through direct expression or administration of specific factors or co-culture approaches with other tissues. Ultimately, through a greater understanding of motor neuron biology, it will be possible to establish more reliable models of ALS. These in turn will have a greater chance of validating new drugs that may be effective for the disease.

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Loss of motoneuron-specific microRNA-218 causes systemic neuromuscular failure

Cited by 130 publications

References 30 publications

ISL1-based LIM complexes control Slit2 transcription in developing cranial motor neurons

ISL1-based LIM complexes control Slit2 transcription in developing cranial motor neurons

MicroRNAs in neural development: from master regulators to fine-tuners

Modeling ALS with motor neurons derived from human induced pluripotent stem cells

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