Distal-Less Makes the Leap

HIGHLIGHTS

DEVELOPMENTAL BIOLOGY limb defect called split-hand/foot IN BRIEF malformation type 1 (SHFM1). In this dominantly inherited disorder, Distal-less makes the central limb digits are missing, CLONING giving the extremities a claw-like the leap appearance. The phenotype of Oct4 distribution and level in mouse clones: Dlx5/6 double-knockout mice, consequences for pluripotency. We’re reminded almost daily that we which these authors generated, Boiani, M. et al. Genes Dev. 16, 1209–219 (2002) are more like our winged, fruit- confirm their expectation that The transcription factor Oct4 is essential for early embryonic craving little friends than Dlx5/6 might regulate limb appearances might first suggest. The development. Not only do these mouse development and is expressed only during embryogenesis latest knock to our dignity comes animals have bone, inner ear and and in germ cells. It is, therefore, a good marker to assess genome from Raymond Robledo and severe craniofacial defects — as reprogramming in cloned blastocysts derived from somatic-cell colleagues, who have found that a could be predicted from the nuclei. Here, Boiani et al. report that cultured cells derived from family of genes homologous to expression patterns of Dlx5/6 and cloned blastocysts that were generated from cumulus-cell nuclei those that control the outgrowth of as has been reported for other Dlx rarely express Oct4 correctly or at levels required for normal antennae and legs in Drosophila also single- and double-knockout mice embryonic development. The frequency of this abnormal patterns limbs in mammals. The — but also they phenocopy the expression alone can account for the low rates of post- Distal-less (Dll )/Dlx family of limb defects seen in human implantation survival of clones. homeobox transcription factors are SHFM1. known for being involved in limb However, Dlx genes can only be MULTIFACTORIAL GENETICS formation in many insects and said to be functional homologues vertebrates; the importance of this of Dll if the limb abnormalities of Simultaneous detection and fine mapping of quantitative study has been to extend this Dlx5/6−/− mice arise from defects trait loci in mice using heterogeneous stocks. function to mammals as well, in proximal–distal (P/D) Mott, R. & Flint, J. Genetics 160, 1609–1618 (2002) including humans. patterning. Indeed, by embryonic Determining the molecular basis of a quantitative trait remains a In Drosophila, there is only one day 11.5 — when most of the challenge as current protocols for fine-mapping QTL involve Dll gene; flies without it lack the mutant defects become apparent scoring a large number of individuals or following the trait over distal portion of their appendages. — all the molecular markers for many generations. The authors have used a computer simulation Mammals, by contrast, have six Dlx the distal medial limb are missing. to show that, by examining only ~1,500 F progeny from a cross genes (Dlx1–Dlx6), which cluster in The authors propose that, by 2 between an inbred line and a heterogeneous stock of mouse (a pairs on the genome — Robledo reducing cell proliferation, the genetic mosaic of eight known strains), a QTL can be mapped to et al. concentrate here on the Dlx5/6 absence of Dlx5/6 causes loss of within ~3 cM by screening with ~100 markers followed by a cluster. This is because, although all cells in the apical ectodermal ridge focused scan on the candidate regions. vertebrate Dlx genes are expressed (AER), which controls P/D in the developing limbs, the brain patterning. Furthermore, the GENE REGULATION and the craniofacial primordia, the ectopic expression of Dlx5 (alone) Dlx5/6 cluster also maps to a region in the AER fully rescued the Identification of tissue-specific microRNAs from mouse. on human chromosome 7 that is SHFM1 defect in Dlx5/6−/− mice. associated with a severe human Putting all this information Lagos-Quintana, M. et al. Curr. Biol. 12, 735–739 (2002) together, Robledo and colleagues MicroRNAs (miRNAs) are non-coding RNAs that are thought to argue that all species with modulate gene expression at the post-transcriptional level. Here, appendages owe these structures to the authors report the identification and cloning of 34 novel the evolutionarily ancient Dll/Dlx miRNAs from mouse, many of which are conserved in other gene family. By showing that Dlx5/6 vertebrate genomes, including human. Many of these miRNAs are mutant mice can phenocopy expressed in a tissue-specific manner, perhaps indicating their SHFM1, they have extended the involvement in tissue specification or cell-lineage decisions. function of Dlx genes to humans, as well as creating a model for GENE EXPRESSION investigating the physiological basis and progression of this human limb Regulation of noise in the expression of a single gene. abnormality. Ozbudak, E. M. et al. Nature Genet. 31, 69–73 (2002) Tanita Casci Biochemical reactions are sensitive to changes in molecular References and links ORIGINAL RESEARCH PAPER Robledo, R. F. concentrations. By measuring the expression levels of a fluorescent et al. The Dlx5 and Dlx6 homeobox genes are reporter gene on a Bacillus subtilis chromosome in different essential for craniofacial, axial, and appendicular Embryonic expression of Dlx5/6 (shown here by translational and transcriptional mutants, the authors quantify the β-galactosidase staining) in a wild-type mouse at skeletal development. Genes Dev. 16, 1089–1101 embryonic day 11.5. Image courtesy of Thomas (2002) extent to which molecular fluctuations in single cells explain the Lufkin, Mount Sinai School of Medicine, USA. WEB SITE differences in gene expression in a genetically identical population Reproduced with permission from Robledo et al. Thomas Lufkin’s lab: http://adsr13.mssm.edu/ Genes & Development © (2002) Cold Spring domains/dept/facultyInfo.epl?objname=biomol (which they call “phenotypic variation”). Their results show that Harbor Laboratory Press. &user=lufkit01 translational efficiency is the main source of phenotypic variation.