What's cooking with cordon-bleu?

Neurulation entails a coordinated sequence of cell movements and rearrangements, culminating in fusion of the neural folds at the dorsal-most point of the neural tube. The molecular pathways that regulate these morphogenetic events are gradually being elucidated, and in Developmental Biology, Carroll and colleagues report on the characterization of cordon-bleu (Cobl), a gene that seems to be required for neural tube closure in the midbrain.

The Cobl locus was originally identified in the mid-1990s in a mouse gene trap screen. The mutant allele, which contained a lacZ gene insertion, was named Cobl^C101. Analysis of the mutant embryos provided few clues as to the function of Cobl, as neither heterozygous nor homozygous Cobl^C101 mutants showed an abnormal phenotype. The Cobl^C101 locus can produce wild-type Cobl mRNA, although Carroll et al. showed that the level of transcription is reduced in homozygous mutants, indicating that the Cobl^C101 allele is hypomorphic rather than null.

The Cobl gene is expressed in the ventral neural tube during neurulation, and Carroll et al. investigated whether it has a role in this process. They examined the effects of the Cobl^C101 mutation in embryos that were also mutant for the loop-tail ( Lp ) gene. Homozygous Lp mutants show failure of neural tube closure from the hindbrain to the caudal end of the embryo, whereas the heterozygotes show the milder looped tail phenotype that gave the mutant its name. Carroll et al. found that in around 20% of embryos that were homozygous for Cobl^C101 and heterozygous for the Lp mutation (Cobl^C101/Cobl^C101;Lp/+), the neural tube also remained open in the midbrain region.

Although Cobl is expressed in the dorsal midbrain from around embryonic day (E) 11.5, this is too late to account for the mutant phenotype, which is evident by E9.5. So, it is probable that Cobl acts more ventrally to influence neural tube closure. The product of the Lp locus, Vangl2, acts as an antagonist of the ventrally-derived signalling molecule sonic hedgehog (Shh), and the authors postulate that Cobl provides additional inhibition of Shh activity. Shh inhibits the development of the dorsolateral hinge point, which generates inward curvature of the neural plate, and the morphology of the Cobl^C101/Cobl^C101;Lp/+ midbrain was consistent with a defect in this process.

Now that the Cobl locus has been fully characterized, it should be possible to generate a null mutant so that its role in neurulation can be investigated in more detail. Interestingly, the structure of the Cobl gene indicates that it belongs to an entirely new family of genes. A related gene — Coblr1 — has already been identified in mice, and there are also Cobl homologues in many other vertebrate species. The finding of Carroll et al. should stimulate further research into this intriguing gene family.