Stem cells outside the bulge

Skin and its associated appendages are replenished by one or more resident stem cell populations. At least one such dedicated stem cell population resides in the bulge region of the hair follicle, but it was unclear whether bulge cells give rise to both hair follicles and interfollicular epidermis or whether a separate epidermal stem cell exists outside the bulge region. Bruce Morgan and colleagues (Dev. Cell 9, 855–861; 2005) now show that hair follicles and interfollicular epidermis are indeed replenished by distinct stem cell populations. The authors crossed the R26R reporter strain to mice expressing GFP-Cre under the control of Shh regulatory elements, permanently marking all Shh-expressing cells and their derivatives with lacZ. Shh is expressed in the epidermal placodes of hair follicles and in a subset of cells in the cycling portion of the follicle but is absent from the interfollicular epidermis at all stages of development. Most cells in adult hair follicles were labeled in the transgenic mice, indicating that the bulge stem cell population was effectively marked, but the interfollicular epidermis remained unlabeled, pointing to the existence of a distinct epidermal stem cell population. KV

Avoiding microRNAs

Much of the investigation into the functions of microRNAs has focused on their role in silencing transcripts that have many target sites, leading to a model in which microRNAs act as development switches. A new study from Stephen Cohen and colleagues (Cell, published online 1 December 2005; 10.1016/S0092867405012729) challenges this model for many Drosophila microRNA targets. They show that only 5% of predicted microRNA targets have more than one target site for any single microRNA, whereas 50% have target sites for two or more microRNAs. A large proportion of transcripts ('antitargets') have no target sites. This polar distribution suggests selection to acquire or eliminate target sites. Targets are enriched for functions in developmental processes, whereas antitargets are enriched for functions in basic cellular processes, such as ribosomal function. Analysis of expression patterns showed a pattern of mutually exclusive expression; gene sets that show tissue-specific expression avoid target sites for microRNAs expressed in the same tissue type but are enriched for target sites for non-coexpressed microRNAs. The authors thus propose that many microRNAs function to suppress erroneously expressed transcripts, akin to a sponge for leaky transcription. Because many transcripts have single target sites for many microRNAs, they predict that many microRNA mutants might show only mild phenotypes. EN

PCP proteins regulate cell packing

Many specialized epithelial tissues are organized as highly ordered arrays of regularly packed cells, but the mechanisms regulating this ordered packing are poorly understood. Suzanne Eaton and colleagues (Dev. Cell 9, 805–817; 2005) now show that repacking of cells during Drosophila wing development is regulated by the same network of proteins that controls the subsequent planar polarization of cells along the wing's proximal-distal axis. They found that the transition to an ordered quasihexagonal array of cells in the developing wing was driven by local remodeling of cellular contacts mediated by a dynamin-based endosome recycling pathway. Notably, this repacking was found to be disturbed in several classical mutants in the planar cell polarity (PCP) pathway. Two core PCP proteins, Flamingo (Fmi) and Frizzled, showed a polarized distribution in cells before initiation of the remodeling process, and Sec5-positive exocytic vesicles were found to be enriched near Fmi-positive cell boundaries. Fmi overexpression led to further accumulation of Sec5-positive vesicles and recruitment of these vesicles to sites of Fmi localization. These findings suggest that the role of the PCP pathway in diverse morphogenetic processes is mediated, in part, through the local regulation of polarized intracellular trafficking events. KV

Efficient nuclear transfer

Long before Dolly, nuclear transfer experiments using frog eggs revealed that nuclei from differentiated cells can be successfully reprogrammed to become totipotent and support development. The chances of success could be increased by serial nuclear transfers in which the donor nucleus was transferred to an enucleated egg, allowed to divide, and then used as a donor again. The nuclei from differentiated cells were observed to replicate very slowly compared to rapid replication when sperm nuclei were used for transfer. Now Marcel Méchali and colleagues report a new way to increase the efficiency of nuclear transfer in frogs (Cell 123, 787–801; 2005). They showed that pre-exposure of differentiated nuclei to mitotic cell extracts bypassed the need for serial transfer and allowed differentiated nuclei to replicate just as rapidly as sperm nuclei. The exposure to mitotic extracts caused an increase in the number of replication origins, a decrease in the spacing between origins and a decrease in the distance that chromatin loops away from the nuclear matrix. These changes required availability of topoisomerase II and acetylated histones. The authors propose that the critical outcome of exposure to mitotic extracts is the organization of the donor nucleus into metaphase chromosomes, which causes a dramatic alteration of chromatin architecture, allowing the donor nucleus to replicate rapidly. EN

Candidate screening with epistasis

Incorporating testing for gene-gene interactions within association studies has been an area of recent interest, with studies exploring both parametric and nonparametric approaches on candidate genes as well as whole-genome association studies. A new study by Josh Millstein and colleagues (Am. J. Hum. Genet. 78, 15–27; 2006) considers an approach that may be useful in incorporating gene interactions into candidate gene case control association studies, tested under several models combining varying main and interaction effects. Their approach is geared towards first selecting a set of candidate loci to test, screening to reduce the number of gene sets tested for higher order interactions (as this can be computationally intensive and lead to problems of multiple testing) and then testing for association under several different models of interaction. The initial screening involves a χ2 statistic used to rank the genes and select subsets considered more likely to show interactions. The testing framework involves a series of stages, testing first for main effects and then sequentially incorporating first and higher orders of interaction. The authors demonstrate that their approach controls type I error rates and provides increased power for detecting candidate genes compared with marginal models and previous nonparametric multifactor dimensionality reduction (or MDR) methods. OB

Research Highlights written by Orli Bahcall, Emily Niemitz and Kyle Vogan.