The hereditary neurodegenerative disease spinal muscular atrophy (SMA) with childhood onset is one of the most common genetic causes of infant mortality. The disease is characterized by selective loss of spinal cord motor neurons leading to muscle atrophy and is the result of mutations in the survival motor neuron (SMN) gene. The SMN protein has been implicated in diverse nuclear processes including splicing, ribosome formation and gene transcription. Even though the genetic basis of SMA is well (...) understood, it is not clear how defects in these ubiquitous processes result in motor neuron degeneration leaving other tissues unaffected. Recent evidence from animal and cell culture models of SMA points to roles for SMN in neurite outgrowth and axonal transport. Disruption of these functions might be particularly detrimental to motor neurons given their high metabolic demands and precise connectivity requirements, thus providing a possible explanation for the specificity of motor neuron susceptibility in SMA. Understanding the molecular mechanisms of SMN activity in neuronal processes may generate new targets for future therapeutic strategies. BioEssays 27:946–957, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Gemins 2–8 and Unr‐interacting protein (UNRIP) are intimate partners of the survival motor neuron (SMN) protein, which is the determining factor for the neuromuscular disorder spinal muscular atrophy (SMA). The most documented role of SMN, Gemins and UNRIP occurs within the large macromolecular SMN complex and involves the cytoplasmic assembly of spliceosomal uridine‐rich small nuclear ribonucleoproteins (UsnRNPs), a housekeeping process critical in all cells. Several reports detailing alternative functions for SMN in either motor neurons or skeletal (...) muscles may, however, hold the answer to the extreme neuromuscular tissue specificity observed in SMA. Recent discoveries indicate that collaboration between SMN and Gemins also extends to these non‐canonical functions, hence raising the possibility that mutations in Gemin genes may be the cause of unlinked neuromuscular hereditary syndromes. This review evaluates the functions of Gemins and UNRIP inside the SMN complex and discusses whether these less notorious SMN complex members are capable of acting independently of SMN. (shrink)

The noncoding RNA 7SK is a critical regulator of transcription by adjusting the activity of the kinase complex P‐TEFb. Release of P‐TEFb from 7SK stimulates transcription at many genes by promoting productive elongation. Conversely, P‐TEFb sequestration by 7SK inhibits transcription. Recent studies have shown that 7SK functions are particularly important for neuron development and maintenance and it can thus be hypothesized that 7SK is at the center of many signaling pathways contributing to neuron function. 7SK activates neuronal gene (...) expression programs that are key for terminal differentiation of neurons. Proteomics studies revealed a complex protein interactome of 7SK that includes several RNA‐binding proteins. Some of these novel 7SK subcomplexes exert non‐canonical cytosolic functions in neurons by regulating axonal mRNA transport and fine‐tuning spliceosome production in response to transcription alterations. Thus, a picture emerges according to which 7SK acts as a multi‐functional RNA scaffold that is integral for neuron homeostasis. (shrink)

Invertebrate genetic models with their tractable neuromuscular systems are effective vehicles for the study of human nerve and muscle disorders. This is exemplified by insights made into spinal muscular atrophy (SMA) using the fruit fly Drosophila melanogaster and the nematode worm Caenorhabditis elegans. For speed and economy, these invertebrates offer convenient, whole‐organism platforms for genetic screening as well as RNA interference (RNAi) and chemical library screens, permitting the rapid testing of hypotheses related to disease mechanisms and the exploration of new (...) therapeutic routes and drug candidates. Here, we discuss recent developments encompassing synaptic physiology, RNA processing, and screening of compound and genome‐scale RNAi libraries, showcasing the importance of invertebrate SMA models.Editor's suggested further reading in BioEssays: SMN and Gemins: ‘We are family’... or are we? Abstract. (shrink)