A rapid and dynamic role for FMRP in the plasticity of adult neurons.

Fragile X syndrome (FXS) is a neuro-developmental disorder caused by silencing Fmr1, which encodes the RNA-binding protein FMRP. Although Fmr1 is expressed in adult neurons, it has been challenging to separate acute from chronic effects of loss of Fmr1 in models of FXS. We have used the precision of Drosophila genetics to test if Fmr1 acutely affects adult neuronal plasticity in vivo, focusing on the s-LNv circadian pacemaker neurons that show 24 hour rhythms in structural plasticity. We found that over-expressing Fmr1 for only 4 hours blocks the activity-dependent expansion of s-LNv projections without altering the circadian clock or activity-regulated gene expression. Conversely, acutely reducing Fmr1 expression prevented s-LNv projections from retracting. One FMRP target that we identified in s-LNvs is sif, which encodes a Rac1 GEF. Our data indicate that FMRP normally reduces sif mRNA translation at dusk to reduce Rac1 activity. Overall, our data reveal a previously unappreciated rapid and direct role for FMRP in acutely regulating neuronal plasticity in adult neurons, and underscore the importance of RNA-binding proteins in this process.

Overexpression of Lin28a delays Xenopus metamorphosis and down-regulates albumin independently of its translational regulation domain.

BACKGROUND: Lin28 regulates stem cell biology and developmental timing. At the molecular level Lin28 inhibits the biogenesis of the micro RNA let-7 and directly controls the transcription and translation of several genes. In Xenopus, Lin28 overexpression delays metamorphosis and affects the expression of genes of the thyroid hormone (TH) axis. The TH carrier albumin, synthesized by the liver, is down-regulated in limbs and tail after Lin28 overexpression. The molecular mechanisms underlying the interaction between Lin28, let-7, and the hypothalamus-pituitary-thyroid gland (HPT) axis are unknown. RESULTS: We found that precursor and mature forms of let-7 increase during Xenopus metamorphosis. In the liver, lin28b is down-regulated and albumin is up-regulated during metamorphosis. Overexpression of a truncated form of Lin28a (Lin28aΔC), which has been shown not to interact with RNA helicase A to regulate translation, delays metamorphosis, indicating that the translational regulation domain is not required to inhibit the HPT axis. Importantly, both full length Lin28a and Lin28aΔC block the increase of albumin mRNA in the liver independently of changes in TH signaling. CONCLUSIONS: These results suggest that Lin28 delays metamorphosis through regulation of let-7 and that the decrease of the TH carrier albumin is one of the early changes after Lin28 overexpression.

The heterochronic gene Lin28 regulates amphibian metamorphosis through disturbance of thyroid hormone function.

Metamorphosis is a classic example of developmental transition, which involves important morphological and physiological changes that prepare the organism for the adult life. It has been very well established that amphibian metamorphosis is mainly controlled by Thyroid Hormone (TH). Here, we show that the heterochronic gene Lin28 is downregulated during Xenopus laevis metamorphosis. Lin28 overexpression before activation of TH signaling delays metamorphosis and inhibits the expression of TH target genes. The delay in metamorphosis is rescued by incubation with exogenous TH, indicating that Lin28 works upstream or parallel to TH. High-throughput analyses performed before any delay on metamorphosis or change in TH signaling showed that overexpression of Lin28 reduces transcript levels of several hormones secreted by the pituitary, including the Thyroid-Stimulating Hormone (TSH), and regulates the expression of proteins involved in TH transport, metabolism and signaling, showing that Lin28 disrupts TH function at different levels. Our data demonstrates that the role of Lin28 in controlling developmental transitions is evolutionary conserved and establishes a functional interaction between Lin28 and thyroid hormone function introducing a new regulatory step in perinatal development with implications for our understanding of endocrine disorders.