BACKGROUND: It has been shown that mutations in at least four myotubularin 
family genes (MTM1, MTMR1, 2 and 13) are causative for human neuromuscular 
disorders. However, the pathway and regulative mechanism remain unknown.
METHODOLOGY/PRINCIPAL FINDINGS: Here, we reported a new role for Mtmr8 in 
neuromuscular development of zebrafish. Firstly, we cloned and characterized 
zebrafish Mtmr8, and revealed the expression pattern predominantly in the eye 
field and somites during early somitogenesis. Using morpholino knockdown, then, 
we observed that loss-of-function of Mtmr8 led to defects in somitogenesis. 
Subsequently, the possible underlying mechanism and signal pathway were 
examined. We first checked the Akt phosphorylation, and observed an increase of 
Akt phosphorylation in the morphant embryos. Furthermore, we studied the PH/G 
domain function within Mtmr8. Although the PH/G domain deletion by itself did 
not result in embryonic defect, addition of PI3K inhibitor LY294002 did give a 
defective phenotype in the PH/G deletion morphants, indicating that the PH/G 
domain was essential for Mtmr8's function. Moreover, we investigated the 
cooperation of Mtmr8 with PI3K in actin filament modeling and muscle 
development, and found that both Mtmr8-MO1 and Mtmr8-MO2+LY294002 led to the 
disorganization of the actin cytoskeleton. In addition, we revealed a possible 
participation of Mtmr8 in the Hedgehog pathway, and cell transplantation 
experiments showed that Mtmr8 worked in a non-cell autonomous manner in actin 
modeling.
CONCLUSION/SIGNIFICANCE: The above data indicate that a conserved functional 
cooperation of Mtmr8 with PI3K regulates actin filament modeling and muscle 
development in zebrafish, and reveal a possible participation of Mtmr8 in the 
Hedgehog pathway. Therefore, this work provides a new clue to study the 
physiological function of MTM family members.