The zebrafish bobtail mutation identifies the MOCS1 (the molybdenum cofactor synthesis step-1) gene that is required for the posterior body formation as an essential element of the Fgf/ERK signaling

Kishimoto Y(1), Koshida S(2), Furutani-Seiki M(3), Kawakami A(4), Reiss J(5), Schwarz G(6), Kohara Y(1), Kondoh H(3,7), Kawakami K(1)

1) National Institute of Genetisc, 2)National Institute of Natural Science, 3)ERATO/SORST JST, 4)Tokyo Institute of Technology, 5)Goettingen Univ., 6)Univ. of Cologne, 7)Osaka Univ.

 The formation of vertebrate posterior body and tail requires coordinated growth, differentiation and movement of multipotent progenitor cells located in the tailbud, and is dependent upon the Fgf signaling. Here we describe the zebrafish bobtail (btl) mutation that exhibits a recessive maternal effect, causing a strong reduction of the tail region and abnormal somite patterning. Through positional cloning, we show that the gene mutated in the btl mutant is a zebrafish homologue of the molybdenum cofactor synthesis step-1 (MOCS1) gene. In humans, mutations in MOCS1 have been described for a lethal genetic disorder, molybdenum cofactor deficiency. MOCS1 catalyzes conversion of GTP to cyclic pyranopterin monophosphate (cPMP), a biosynthetic intermediate for molybdenum cofactor. Injection of cPMP at the one-cell stage completely rescued the btl mutant phenotype, demonstrating that the defects in the btl mutant are caused by the lack of cPMP biosynthesis. Furthermore, we found that phosphorylation of the ERK protein in the tailbud region, which has been shown to be regulated through the Fgf signaling, strongly decreased during gastrulation and segmentation stages in the btl mutant embryos. Implantation of Fgf-soaked beads could not induce ectopic ERK phosphorylation in the btl mutant, indicating that MOCS1 is required for Fgf-dependent ERK activation. Our results suggest a molecular link between molybdenum cofactor biosynthesis and Fgf/ERK signaling during the development of the vertebrate posterior structures.