Another fly PCP gene has a conserved role in mice

Dev Biol. 2010 Jan 11. [Epub ahead of print]

PCP effector gene Inturned is an important regulator of cilia formation and embryonic development in mammals

Zeng H, Hoover AN, Liu A.

Department of Biology, Eberly College of Science, The Pennsylvania State University, University Park, PA 16802, USA.

The PCP effector gene Inturned regulates planar cell polarity (PCP) and wing hair formation in Drosophila wings. In order to understand the roles for Inturned in mammalian embryonic development, we generated a null mutant allele for the mouse homologue of Inturned (Intu) via gene-targeting in ES cells. Mouse Intu null mutants are homozygous lethal at midgestation, exhibiting multiple defects including neural tube closure defects, abnormal dorsal/ventral patterning of the central nervous system and abnormal anterior-posterior patterning of the limbs resulting in severe polydactyly (7-9 digits each limb). The developmental processes affected by the Intu mutation are under the control of Hh signaling through Gli-family transcription factors. We found that in Intu mutant embryos the expression of Gli1 and Ptch1, two direct transcriptional targets of Hh signaling, is down-regulated, and the proteolytic processing of Gli3 is compromised. We further demonstrate that Intu plays significant roles in the formation of primary cilia both during embryonic development and in cultured fibroblasts. Finally, a cytoplasmic GFP-Intu fusion protein efficiently rescues the ciliogenic defects in Intu mutant cells. In conclusion, we show that PCP effector gene Intu is an important regulator of cilia formation, Hh signal transduction, and embryonic development in mammals. Copyright © 2010 Elsevier Inc. All rights reserved.

Hippo is also a tumour suppressor in mammals

The Hippo signalling pathway is conserved between flies and humans, but whether Hippo's function as a tumour suppressor in flies also holds in mammals was not known. This paper reports that the MST1/2 double knockout is embryonic lethal in mice and that post-natal removal of the genes causes liver tumours.

Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1431-6. Epub 2010 Jan 8.

Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression.

Song H, Mak KK, Topol L, Yun K, Hu J, Garrett L, Chen Y, Park O, Chang J, Simpson RM, Wang CY, Gao B, Jiang J, Yang Y.

Genetic Disease Research Branch, National Human Genome Research Institute, Bethesda, MD 20892.

Control of organ size by cell proliferation and survival is a fundamental developmental process, and its deregulation leads to cancer. However, the molecular mechanism underlying organ size control remains elusive in vertebrates. In Drosophila, the Hippo (Hpo) signaling pathway controls organ size by both restricting cell growth and proliferation and promoting cell death. Here we investigated whether mammals also require the Hpo pathway to control organ size and adult tissue homeostasis. We found that Mst1 and Mst2, the two mouse homologs of the Drosophila Hpo, control the sizes of some, but not all organs, in mice, and Mst1 and Mst2 act as tumor suppressors by restricting cell proliferation and survival. We show that Mst1 and Mst2 play redundant roles, and removal of both resulted in early lethality in mouse embryos. Importantly, tumors developed in the liver with a substantial increase of the stem/progenitor cells by 6 months after removing Mst1 and Mst2 postnatally. We show that Mst1 and Mst2 were required in vivo to control Yap phosphorylation and activity. Interestingly, apoptosis induced by TNFalpha was blocked in the Mst1 and Mst2 double-mutant cells both in vivo and in vitro. As TNFalpha is a pleiotropic inflammatory cytokine affecting most organs by regulating cell proliferation and cell death, resistance to TNFalpha-induced cell death may also contribute significantly to tumor formation in the absence of Mst1 and Mst2.

Planar cell polarity meets membrane trafficking

In an interesting new finding, Rab23 - a presumed regulator of membrane traffic - is required for planar cell polarity in Drosophila. Rab23 has a 'multiple wing hair' type phenotype and affects the polarized distribution of protiens such as Vang and Prickle.

Genetics. 2010 Feb 1. [Epub ahead of print]

Drosophila Rab23 is Involved in the Regulation of the Number and Planar Polarization of the Adult Cuticular Hairs.

Pataki C, Matusek T, Kurucz E, Andó I, Jenny A, Mihály J.

HAS: BRC Institute of Genetics.

The planar coordination of cellular polarization is an important, yet not well understood aspect of animal development. In a screen for genes regulating planar cell polarization in Drosophila, we identified Rab23, encoding a putative vesicular trafficking protein. Mutations in the Drosophila Rab23 orthologue result in abnormal trichome orientation and the formation of multiple hairs on the wing, leg and abdomen. We show that Rab23 impairs hexagonal packing of the wing cells, and that it plays a role in cortical polarization of the polarity proteins. We found that Rab23 is able to associate with the proximally accumulated Prickle protein, although Rab23 itself does not appear to display a polarized subcellular distribution in wing cells. The absence of Rab23 leads to increased actin accumulation in the sub-apical region of the pupal wing cells that fail to restrict prehair initiation to a single site. Rab23 acts as a dominant enhancer of the weak multiple hair phenotype exhibited by the core polarity mutations, whereas the Rab23 homozygous mutant phenotype is sensitive to the gene dose of the planar polarity effector genes. Together, our data suggest that Rab23 contributes to the mechanism that inhibits hair formation at positions outside of the distal vertex by activating the planar polarity effector system.

High Flyers takes off

High Flyers collects Barry Thompson's picks of the best recent breakthroughs in Drosophila biology. Links to outstanding papers will be posted, along with a brief outline of the discovery and its significance to the field.