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Gamma and alpha motor neurons distinguished by expression of transcription factor Err3.

ABSTRACT: Spinal motor neurons are specified to innervate different muscle targets through combinatorial programs of transcription factor expression. Whether transcriptional programs also establish finer aspects of motor neuron subtype identity, notably the prominent functional distinction between alpha and gamma motor neurons, remains unclear. In this study, we identify DNA binding proteins with complementary expression profiles in alpha and gamma motor neurons, providing evidence for molecular distinctions in these two motor neuron subtypes. The transcription factor Err3 is expressed at high levels in gamma but not alpha motor neurons, whereas the neuronal DNA binding protein NeuN marks alpha but not gamma motor neurons. Signals from muscle spindles are needed to support the differentiation of Err3(on)/NeuN(off) presumptive gamma motor neurons, whereas direct proprioceptive sensory input to a motor neuron pool is apparently dispensable. Together, these findings provide evidence that transcriptional programs define functionally distinct motor neuron subpopulations, even within anatomically defined motor pools.

SUBMITTER: Friese A

PROVIDER: S-EPMC2716387 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:We hypothesised that differences in microRNA expression profiles contribute to the contrasting natural history and clinical outcome of the two most common types of malignant germ cell tumour (GCT), yolk sac tumours (YSTs) and germinomas. RESULTS:By direct comparison, using microarray data for paediatric GCT samples and published qRT-PCR data for adult samples, we identified microRNAs significantly up-regulated in YSTs (n = 29 paediatric, 26 adult, 11 overlapping) or germinomas (n = 37 paediatric). By Taqman qRT-PCR we confirmed differential expression of 15 of 16 selected microRNAs and further validated six of these (miR-302b, miR-375, miR-200b, miR-200c, miR-122, miR-205) in an independent sample set. Interestingly, the miR-302 cluster, which is over-expressed in all malignant GCTs, showed further over-expression in YSTs versus germinomas, representing six of the top eight microRNAs over-expressed in paediatric YSTs and seven of the top 11 in adult YSTs. To explain this observation, we used mRNA expression profiles of paediatric and adult malignant GCTs to identify 10 transcription factors (TFs) consistently over-expressed in YSTs versus germinomas, followed by linear regression to confirm associations between TF and miR-302 cluster expression levels. Using the sequence motif analysis environment iMotifs, we identified predicted binding sites for four of the 10 TFs (GATA6, GATA3, TCF7L2 and MAF) in the miR-302 cluster promoter region. Finally, we showed that miR-302 family over-expression in YST is likely to be functionally significant, as mRNAs down-regulated in YSTs were enriched for 3' untranslated region sequences complementary to the common seed of miR-302a~miR-302d. Such mRNAs included mediators of key cancer-associated processes, including tumour suppressor genes, apoptosis regulators and TFs. CONCLUSIONS:Differential microRNA expression is likely to contribute to the relatively aggressive behaviour of YSTs and may enable future improvements in clinical diagnosis and/or treatment.

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Gamma and alpha motor neurons distinguished by expression of transcription factor Err3.

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