Autosomal recessive spinal muscular atrophy (SMA) is linked to mutations in the survival motor neuron (SMN) gene. The SMN protein has been implicated at several levels of mRNA biogenesis and is expressed ubiquitously. Studies in various model organisms have shown that the loss of function of the SMN gene leads to embryonic lethality. The human contains two genes encoding for SMN protein and in patients one of these is disrupted. It is thought the remaining low levels of protein produced by the second SMN gene do not suffice and result in the observed specific loss of lower motor neurons and muscle wasting. The early lethality in the animal mutants has made it difficult to understand why primarily these tissues are affected. We have isolated a Drosophila smn mutant. The fly alleles contain point mutations in smn similar to those found in SMA patients. We find that zygotic smn mutant animals show abnormal motor behavior and that smn gene activity is required in both neurons and muscle to alleviate this phenotype. Physiological experiments on the fly smn mutants show that excitatory post-synaptic currents are reduced while synaptic motor neuron boutons are disorganized, indicating defects at the neuromuscular junction. Clustering of a neurotransmitter receptor subunit in the muscle at the neuromuscular junction is severely reduced. This new Drosophila model for SMA thus proposes a functional role for SMN at the neuromuscular junction in the generation of neuromuscular defects.

Acute liver injury is a common disease without effective therapy in humans. We sought to evaluate a combination therapy of insulin‐like growth factor 1 (IGF‐I) and BTP‐2 in a mouse liver injury model induced by lipopolysaccharide (LPS). We chose this model because LPS is known to increase the expression of the transcription factors related to systemic inflammation (i.e., NFκB, CREB, AP1, IRF 3, and NFAT), which depends on calcium signaling. Notably, these transcription factors all have pleiotropic effects and account for the other observed changes in tissue damage parameters. Additionally, LPS is also known to increase the genes associated with a tissue injury (e.g., NGAL, SOD, caspase 3, and type 1 collagen) and systemic expression of pro‐inflammatory cytokines. Finally, LPS compromises vascular integrity. Accordingly, IGF‐I was selected because its serum levels were shown to decrease during systemic inflammation. BTP‐2 was chosen because it was known to decrease cytosolic calcium, which is increased by LPS. This current study showed that IGF‐I, BTP‐2, or a combination therapy significantly altered and normalized all of the aforementioned LPS‐induced gene changes. Additionally, our therapies reduced the vascular leakage caused by LPS, as evidenced by the Evans blue dye technique. Furthermore, histopathologic studies showed that IGF‐I decreased the proportion of hepatocytes with ballooning degeneration. Finally, IGF‐I also increased the expression of the hepatic growth factor (HGF) and the receptor for the epidermal growth factor (EGFR), markers of liver regeneration. Collectively, our data suggest that a combination of IGF‐I and BTP‐2 is a promising therapy for acute liver injury.

No abstract

No abstract

No abstract