Have Hair Follicle Stem Cells Shed Their Tranquil Image?

In a recent issue of Nature Genetics, Jaks et al. (2008) demonstrate that hair follicle cells expressing the intestinal stem cell marker Lgr5 are hair follicle epithelial stem cells. In contrast to the established bulge stem cell population, Lrg5+ cells are actively cycling and reside in part outside the bulge

Including probe-level uncertainty in model-based gene expression clustering

BACKGROUND: Clustering is an important analysis performed on microarray gene expression data since it groups genes which have similar expression patterns and enables the exploration of unknown gene functions. Microarray experiments are associated with many sources of experimental and biological variation and the resulting gene expression data are therefore very noisy. Many heuristic and model-based clustering approaches have been developed to cluster this noisy data. However, few of them include consideration of probe-level measurement error which provides rich information about technical variability. RESULTS: We augment a standard model-based clustering method to incorporate probe-level measurement error. Using probe-level measurements from a recently developed Affymetrix probe-level model, multi-mgMOS, we include the probe-level measurement error directly into the standard Gaussian mixture model. Our augmented model is shown to provide improved clustering performance on simulated datasets and a real mouse time-course dataset. CONCLUSION: The performance of model-based clustering of gene expression data is improved by including probe-level measurement error and more biologically meaningful clustering results are obtained

Dominant Mutations in GRHL3 Cause Van der Woude Syndrome and Disrupt Oral Periderm Development

Mutations in interferon regulatory factor 6 (IRF6) account for ∼70% of cases of Van der Woude syndrome (VWS), the most common syndromic form of cleft lip and palate. In 8 of 45 VWS-affected families lacking a mutation in IRF6, we found coding mutations in grainyhead-like 3 (GRHL3). According to a zebrafish-based assay, the disease-associated GRHL3 mutations abrogated periderm development and were consistent with a dominant-negative effect, in contrast to haploinsufficiency seen in most VWS cases caused by IRF6 mutations. In mouse, all embryos lacking Grhl3 exhibited abnormal oral periderm and 17% developed a cleft palate. Analysis of the oral phenotype of double heterozygote (Irf6+/−;Grhl3+/−) murine embryos failed to detect epistasis between the two genes, suggesting that they function in separate but convergent pathways during palatogenesis. Taken together, our data demonstrated that mutations in two genes, IRF6 and GRHL3, can lead to nearly identical phenotypes of orofacial cleft. They supported the hypotheses that both genes are essential for the presence of a functional oral periderm and that failure of this process contributes to VWS

Protein kinase C activation disrupts epithelial apical junctions via ROCK-II dependent stimulation of actomyosin contractility

<p>Abstract</p> <p>Background</p> <p>Disruption of epithelial cell-cell adhesions represents an early and important stage in tumor metastasis. This process can be modeled <it>in vitro </it>by exposing cells to chemical tumor promoters, phorbol esters and octylindolactam-V (OI-V), known to activate protein kinase C (PKC). However, molecular events mediating PKC-dependent disruption of epithelial cell-cell contact remain poorly understood. In the present study we investigate mechanisms by which PKC activation induces disassembly of tight junctions (TJs) and adherens junctions (AJs) in a model pancreatic epithelium.</p> <p>Results</p> <p>Exposure of HPAF-II human pancreatic adenocarcinoma cell monolayers to either OI-V or 12-O-tetradecanoylphorbol-13-acetate caused rapid disruption and internalization of AJs and TJs. Activity of classical PKC isoenzymes was responsible for the loss of cell-cell contacts which was accompanied by cell rounding, phosphorylation and relocalization of the F-actin motor nonmuscle myosin (NM) II. The OI-V-induced disruption of AJs and TJs was prevented by either pharmacological inhibition of NM II with blebbistatin or by siRNA-mediated downregulation of NM IIA. Furthermore, AJ/TJ disassembly was attenuated by inhibition of Rho-associated kinase (ROCK) II, but was insensitive to blockage of MLCK, calmodulin, ERK1/2, caspases and RhoA GTPase.</p> <p>Conclusion</p> <p>Our data suggest that stimulation of PKC disrupts epithelial apical junctions via ROCK-II dependent activation of NM II, which increases contractility of perijunctional actin filaments. This mechanism is likely to be important for cancer cell dissociation and tumor metastasis.</p

Dominant Mutations in GRHL3 Cause Van der Woude Syndrome and Disrupt Oral Periderm Development

Peer reviewe

Circadian Clock Genes Contribute to the Regulation of Hair Follicle Cycling

Hair follicles undergo recurrent cycling of controlled growth (anagen), regression (catagen), and relative quiescence (telogen) with a defined periodicity. Taking a genomics approach to study gene expression during synchronized mouse hair follicle cycling, we discovered that, in addition to circadian fluctuation, CLOCK–regulated genes are also modulated in phase with the hair growth cycle. During telogen and early anagen, circadian clock genes are prominently expressed in the secondary hair germ, which contains precursor cells for the growing follicle. Analysis of Clock and Bmal1 mutant mice reveals a delay in anagen progression, and the secondary hair germ cells show decreased levels of phosphorylated Rb and lack mitotic cells, suggesting that circadian clock genes regulate anagen progression via their effect on the cell cycle. Consistent with a block at the G1 phase of the cell cycle, we show a significant upregulation of p21 in Bmal1 mutant skin. While circadian clock mechanisms have been implicated in a variety of diurnal biological processes, our findings indicate that circadian clock genes may be utilized to modulate the progression of non-diurnal cyclic processes

Including probe-level uncertainty in model-based gene expression clustering

BackgroundClustering is an important analysis performed on microarray gene expression data since it groups genes which have similar expression patterns and enables the exploration of unknown gene functions. Microarray experiments are associated with many sources of experimental and biological variation and the resulting gene expression data are therefore very noisy. Many heuristic and model-based clustering approaches have been developed to cluster this noisy data. However, few of them include consideration of probe-level measurement error which provides rich information about technical variability.ResultsWe augment a standard model-based clustering method to incorporate probe-level measurement error. Using probe-level measurements from a recently developed Affymetrix probe-level model, multi-mgMOS, we include the probe-level measurement error directly into the standard Gaussian mixture model. Our augmented model is shown to provide improved clustering performance on simulated datasets and a real mouse time-course dataset.ConclusionThe performance of model-based clustering of gene expression data is improved by including probe-level measurement error and more biologically meaningful clustering results are obtained