Hot off the presses! Sep 14 dev cell

The Sep 14 issue of the dev cell is now up on Pubget (About dev cell): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Signaling Defects and the Nuclear Envelope in Progeria
  - dev cell 19(3):355-356 (2010)
  Hutchinson-Gilford progeria syndrome is a rare childhood genetic disorder with features of accelerated aging. In this issue, Hernandez et al. observe decreased Wnt signaling and extracellular matrix gene expression in a murine model of the disease, suggesting potential therapeutic strategies and further emphasizing the nuclear envelope's role in signal transduction.
• Multiclassifier Proteomics to Define Complexes Yields New Chromosomal Proteins
  - dev cell 19(3):356-359 (2010)
  In a recent issue of Cell, Ohta et al. report a method of quantitative proteomics coupled with bioinformatic analysis for the identification of associated components in complex mixtures. Using this approach, they assayed the protein composition of mitotic chromosomes, identifying 4029 associated proteins, 562 of which are previously uncharacterized.
• It's Not Just Sex
  - dev cell 19(3):359-360 (2010)
  The dosage of X and Y chromosome genes varies systematically in males and females. In mammals, X inactivation largely compensates for this, but in this issue of Developmental Cell, Wijchers et al. show that the expression of hundreds of autosomal genes is still influenced by sex chromosome dosage, independently of physiological sex.
• pRb, a Switch between Bone and Brown Fat
  - dev cell 19(3):360-362 (2010)
  Calo et al. (2010) recently reported that the absence of the transcriptional regulator pRb enhances differentiation of mesenchymal precursors toward the brown adipocyte lineage in detriment of osteoblast and white fat populations. These findings may have therapeutic implications for cancer and bone and metabolic disease.
• A Cellular View of Nf2 in Liver Homeostasis and Tumorigenesis
  - dev cell 19(3):363-364 (2010)
  How liver adjusts and stabilizes its size is unsolved so far; the answers to this question may also provide insights into mechanisms of hepatocarcinogenesis. Two recent papers suggest a role for Merlin/Nf2 in control of liver cell turnover, but results appear conflicting at first glance.
• A Zyxin-Mediated Mechanism for Actin Stress Fiber Maintenance and Repair
  - dev cell 19(3):365-376 (2010)
  To maintain mechanical homeostasis, cells must recognize and respond to changes in cytoskeletal integrity. By imaging live cells expressing fluorescently tagged cytoskeletal proteins, we observed that actin stress fibers undergo local, acute, force-induced elongation and thinning events that compromise their stress transmission function, followed by stress fiber repair that restores this capability. The LIM protein zyxin rapidly accumulates at sites of strain-induced stress fiber damage and is essential for stress fiber repair and generation of traction force. Zyxin promotes recruitment of the actin regulatory proteins α-actinin and VASP to compromised stress fiber zones. α-Actinin plays a critical role in restoration of actin integrity at sites of local stress fiber damage, whereas both α-actinin and VASP independently contribute to limiting stress fiber elongation at strain sites, thus promoting stabilization of the stress fiber. Our findings demonstrate a mechani! sm for rapid repair and maintenance of the structural integrity of the actin cytoskeleton.
• Rho-Kinase Directs Bazooka/Par-3 Planar Polarity during Drosophila Axis Elongation
  - dev cell 19(3):377-388 (2010)
  Cell rearrangements shape the Drosophila embryo via spatially regulated changes in cell shape and adhesion. We show that Bazooka/Par-3 (Baz) is required for the planar polarized distribution of myosin II and adherens junction proteins and polarized intercalary behavior is disrupted in baz mutants. The myosin II activator Rho-kinase is asymmetrically enriched at the anterior and posterior borders of intercalating cells in a pattern complementary to Baz. Loss of Rho-kinase results in expansion of the Baz domain, and activated Rho-kinase is sufficient to exclude Baz from the cortex. The planar polarized distribution of Baz requires its C-terminal domain. Rho-kinase can phosphorylate this domain and inhibit its interaction with phosphoinositide membrane lipids, suggesting a mechanism by which Rho-kinase could regulate Baz association with the cell cortex. These results demonstrate that Rho-kinase plays an instructive role in planar polarity by targeting Baz/Par-3 and myosi! n II to complementary cortical domains.
• Atypical Cadherins Dachsous and Fat Control Dynamics of Noncentrosomal Microtubules in Planar Cell Polarity
  Harumoto T Ito M Shimada Y Kobayashi TJ Ueda HR Lu B Uemura T - dev cell 19(3):389-401 (2010)
  How global organ asymmetry and individual cell polarity are connected to each other is a central question in studying planar cell polarity (PCP). In the Drosophila wing, which develops PCP along its proximal-distal (P-D) axis, we previously proposed that the core PCP mediator Frizzled redistributes distally in a microtubule (MT)-dependent manner. Here, we performed organ-wide analysis of MT dynamics by introducing quantitative in vivo imaging. We observed MTs aligning along the P-D axis at the onset of redistribution and a small but significant excess of + ends-distal MTs in the proximal region of the wing. This characteristic alignment and asymmetry of MT growth was controlled by atypical cadherins Dachsous (Ds) and Fat (Ft). Furthermore, the action of Ft was mediated in part by PAR-1. All these data support the idea that the active reorientation of MT growth adjusts cell polarity along the organ axis.
• Chiral Forces Organize Left-Right Patterning in C. elegans by Uncoupling Midline and Anteroposterior Axis
  - dev cell 19(3):402-412 (2010)
  Left-right (LR) patterning is an intriguing but poorly understood process of bilaterian embryogenesis. We report a mechanism for LR patterning in C. elegans in which the embryo uncouples its midline from the anteroposterior (AP) axis. Specifically, the eight-cell embryo establishes a midline that is tilted rightward from the AP axis and positions more cells on the left, allowing subsequent differential LR fate inductions. To establish the tilted midline, cells exhibit LR asymmetric protrusions and a handed collective movement. This process, termed chiral morphogenesis, involves differential regulation of cortical contractility between a pair of sister cells that are bilateral counterparts fate-wise and is activated by noncanonical Wnt signaling. Chiral morphogenesis is timed by the cytokinetic furrow of a neighbor of the sister pair, providing a developmental clock and an unexpected signaling interaction between the contractile ring and the adjacent cells.
• Functional Coupling between the Extracellular Matrix and Nuclear Lamina by Wnt Signaling in Progeria
  - dev cell 19(3):413-425 (2010)
  The segmental premature aging disease Hutchinson-Gilford Progeria (HGPS) is caused by a truncated and farnesylated form of Lamin A. In a mouse model for HGPS, a similar Lamin A variant causes the proliferative arrest and death of postnatal, but not embryonic, fibroblasts. Arrest is due to an inability to produce a functional extracellular matrix (ECM), because growth on normal ECM rescues proliferation. The defects are associated with inhibition of canonical Wnt signaling, due to reduced nuclear localization and transcriptional activity of Lef1, but not Tcf4, in both mouse and human progeric cells. Defective Wnt signaling, affecting ECM synthesis, may be critical to the etiology of HGPS because mice exhibit skeletal defects and apoptosis in major blood vessels proximal to the heart. These results establish a functional link between the nuclear envelope/lamina and the cell surface/ECM and may provide insights into the role of Wnt signaling and the ECM in aging.
• Extended-Synaptotagmin-2 Mediates FGF Receptor Endocytosis and ERK Activation In Vivo
  - dev cell 19(3):426-439 (2010)
  Targeting of activated plasma membrane receptors to endocytic pathways is important in determining the outcome of growth factor signaling. However, the molecular mechanisms are still poorly understood. Here, we show that the synaptotagmin-related membrane protein E-Syt2 is essential for rapid endocytosis of the activated FGF receptor and for functional signal transduction during Xenopus development. E-Syt2 depletion prevents an early phase of activated FGF receptor endocytosis that we show is required for ERK activation and the induction of the mesoderm. E-Syt2 interacts selectively with the activated FGF receptor and with Adaptin-2, and is required upstream of Ras activation and of receptor autophosphorylation for ERK activation and the induction of the mesodermal marker Xbra. The data identify E-Syt2 as an endocytic adaptor for the clathrin-mediated pathway whose function is conserved in human and suggest a broader role for the E-Syt subfamily in growth factor signal! ing.
• FGF9 Suppresses Meiosis and Promotes Male Germ Cell Fate in Mice
  - dev cell 19(3):440-449 (2010)
  Sex determination of mammalian germ cells occurs during fetal development and depends on signals from gonadal somatic cells. Previous studies have established that retinoic acid (RA) triggers ovarian germ cells to enter meiosis and thereby commit to oogenesis, whereas in the developing testis, the enzyme CYP26B1 degrades RA and germ cells are not induced to enter meiosis. Using in vitro and in vivo models, we demonstrate that fibroblast growth factor 9 (FGF9) produced in the fetal testis acts directly on germ cells to inhibit meiosis; in addition, FGF9 maintains expression of pluripotency-related genes and upregulates markers associated with male germ cell fate. We conclude that two independent and mutually antagonistic pathways involving RA and FGF9 act in concert to determine mammalian germ cell sexual fate commitment and support a model in which the mitosis/meiosis switch is robustly controlled by both positive and negative regulatory factors.
• Hopx and Hdac2 Interact to Modulate Gata4 Acetylation and Embryonic Cardiac Myocyte Proliferation
  - dev cell 19(3):450-459 (2010)
  Regulation of chromatin structure via histone modification has recently received intense attention. Here, we demonstrate that the chromatin-modifying enzyme histone deacetylase 2 (Hdac2) functions with a small homeodomain factor, Hopx, to mediate deacetylation of Gata4, which is expressed by cardiac progenitor cells and plays critical roles in the regulation of cardiogenesis. In the absence of Hopx and Hdac2 in mouse embryos, Gata4 hyperacetylation is associated with a marked increase in cardiac myocyte proliferation, upregulation of Gata4 target genes, and perinatal lethality. Hdac2 physically interacts with Gata4, and this interaction is stabilized by Hopx. The ability of Gata4 to transactivate cell cycle genes is impaired by Hopx/Hdac2-mediated deacetylation, and this effect is abrogated by loss of Hdac2-Gata4 interaction. These results suggest that Gata4 is a nonhistone target of Hdac2-mediated deacetylation and that Hdac2, Hopx, and Gata4 coordinately regulate car! diac myocyte proliferation during embryonic development.
• Histone Demethylase JmjD2A Regulates Neural Crest Specification
  - dev cell 19(3):460-468 (2010)
  The neural crest is a multipotent stem cell-like population that is induced during gastrulation, but only acquires its characteristic morphology, migratory ability, and gene expression profile after neurulation. This raises the intriguing possibility that precursors are actively maintained by epigenetic influences in a stem cell-like state. Accordingly, we report that dynamic histone modifications are critical for proper temporal control of neural crest gene expression in vivo. The histone demethylase, JumonjiD2A (JmjD2A/KDM4A), is expressed in the forming neural folds. Loss of JmjD2A function causes dramatic downregulation of neural crest specifier genes analyzed by multiplex NanoString and in situ hybridization. Importantly, in vivo chromatin immunoprecipitation reveals direct stage-specific interactions of JmjD2A with regulatory regions of neural crest genes, and associated temporal modifications in methylation states of lysine residues directly affected by JmjD2A a! ctivity. Our findings show that chromatin modifications directly control neural crest genes in vertebrate embryos via modulating histone methylation.
• The Matrix Protein hnRNP U Is Required for Chromosomal Localization of Xist RNA
  - dev cell 19(3):469-476 (2010)
  In XX female mammals, one of the two X chromosomes is epigenetically inactivated to equalize gene expression with XY males. The formation of the inactive X chromosome (Xi) is regulated by an X-linked long noncoding RNA Xist, which accumulates on the entire length of the chromosome in cis and induces heterochromatin formation. However, the mechanism by which Xist RNA "paints" the Xi has long remained elusive. Here, we show that a matrix protein hnRNP U/SP120/SAF-A is required for the accumulation of Xist RNA on the Xi. Xist RNA and hnRNP U interact and upon depletion of hnRNP U, Xist RNA is detached from the Xi and diffusely localized into the nucleoplasm. In addition, ES cells lacking hnRNP U expression fail to form the Xi. We propose that the association with matrix proteins is an essential step in the epigenetic regulation of gene expression by Xist RNA.
• Sexual Dimorphism in Mammalian Autosomal Gene Regulation Is Determined Not Only by Sry but by Sex Chromosome Complement As Well
  - dev cell 19(3):477-484 (2010)
  Differences between males and females are normally attributed to developmental and hormonal differences between the sexes. Here, we demonstrate differences between males and females in gene silencing using a heterochromatin-sensitive reporter gene. Using "sex-reversal" mouse models with varying sex chromosome complements, we found that this differential gene silencing was determined by X chromosome complement, rather than sex. Genome-wide transcription profiling showed that the expression of hundreds of autosomal genes was also sensitive to sex chromosome complement. These genome-wide analyses also uncovered a role for Sry in modulating autosomal gene expression in a sex chromosome complement-specific manner. The identification of this additional layer in the establishment of sexual dimorphisms has implications for understanding sexual dimorphisms in physiology and disease. PaperClip To listen to this audio, enable JavaScript on your browser. However, you can download and play the audio by clicking on the icon below Download this Audio (2130 K)