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Fusarium head blight (FHB) in triticale (× Triticosecale Wittmack) results in yield losses and mycotoxin contamination, for example, by deoxynivalenol (DON). This study aimed to analyse the correlation between FHB severity and DON content in a DH population of 146 entries across environments. Additionally, Fusarium damaged kernel (FDK) rating, heading stage and plant height were recorded. Highly significant (P

V1 and V2b interneurons (INs) are essential for the production of an alternating flexor–extensor motor output. Using a tripartite genetic system to selectively ablate either V1 or V2b INs in the caudal spinal cord and assess their specific functions in awake behaving animals, we find that V1 and V2b INs function in an opposing manner to control flexor–extensor-driven movements. Ablation of V1 INs results in limb hyperflexion, suggesting that V1 IN-derived inhibition is needed for proper extension movements of the limb. The loss of V2b INs results in hindlimb hyperextension and a delay in the transition from stance phase to swing phase, demonstrating V2b INs are required for the timely initiation and execution of limb flexion movements. Our findings also reveal a bias in the innervation of flexor- and extensor-related motor neurons by V1 and V2b INs that likely contributes to their differential actions on flexion–extension movements. DOI: http://dx.doi.org/10.7554/eLife.04718.001, eLife digest Although there are many different movements an animal can make with its limbs—from reaching to walking—they all basically involve two sets of muscles that act as opposing levers around each joint. ‘Flexor’ muscles contract to bend the limb, and ‘extensor’ muscles contract to extend the limb. When an animal is walking these two sets of muscles contract repeatedly, one after the other. Inhibitory neurons in the spinal cord coordinate these walking movements by preventing the flexor or extensor muscles from contracting at the same time. In 2014, researchers discovered that two groups of inhibitory neurons, known as the V1 and V2b interneurons, are essential for this alternating pattern of flexing and extending of the limbs of newborn mice. However, these experiments were not able to assess the particular contribution that the V1 and V2b neurons each make to limb movements. Now, Britz et al.—including several of the researchers involved in the 2014 study—have used a sophisticated genetic technique in mice to investigate the role that each group of neurons plays separately. This involved introducing a gene into either the V1 or V2b neurons that makes them susceptible to being killed with the diphtheria toxin. Injecting the mice with diphtheria toxin selectively removed these cells from the regions of the spinal cord that controls hindlimb movements. Britz et al. found that removing either group of neurons prevented the mice from walking normally. Eliminating the V1 neurons caused extreme flexing of the hindlimbs, revealing that the V1 neurons are needed to extend the limb by inhibiting the motor neurons that contract the flexor muscles. In contrast, the loss of V2b neurons caused exaggerated hindlimb extension, indicating that the V2b neurons inhibit the motor neurons that innervate extensor muscles. Both the V1 and V2b groups of neurons contain a wide range of different cell types. Future studies will therefore need to explore how these different cells are involved in coordinating the motions involved in walking. DOI: http://dx.doi.org/10.7554/eLife.04718.002

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically heterogeneous heart-muscle disorder characterized by progressive fibrofatty replacement of right ventricular myocardium and an increased risk of sudden cardiac death. Mutations in desmosomal proteins that cause ARVC have been previously described; therefore, we investigated 88 unrelated patients with the disorder for mutations in human desmosomal cadherin desmocollin-2 (DSC2). We identified a heterozygous splice-acceptor-site mutation in intron 5 (c.631-2A--G) of the DSC2 gene, which led to the use of a cryptic splice-acceptor site and the creation of a downstream premature termination codon. Quantitative analysis of cardiac DSC2 expression in patient specimens revealed a marked reduction in the abundance of the mutant transcript. Morpholino knockdown in zebrafish embryos revealed a requirement for dsc2 in the establishment of the normal myocardial structure and function, with reduced desmosomal plaque area, loss of the desmosome extracellular electron-dense midlines, and associated myocardial contractility defects. These data identify DSC2 mutations as a cause of ARVC in humans and demonstrate that physiologic levels of DSC2 are crucial for normal cardiac desmosome formation, early cardiac morphogenesis, and cardiac function.

Erythropoietin (EPO) is required for cell survival during differentiation and for progenitor expansion during stress erythropoiesis. Although signaling pathways may couple directly to docking sites on the EPO receptor (EpoR), additional docking molecules expand the signaling platform of the receptor. We studied the roles of the docking molecules Grb2-associated binder-1 (Gab1) and Gab2 in EPO-induced signal transduction and erythropoiesis. Inhibitors of phosphatidylinositide 3-kinase and Src kinases suppressed EPO-dependent phosphorylation of Gab2. In contrast, Gab1 activation depends on recruitment and phosphorylation by the tyrosine kinase receptor RON, with which it is constitutively associated. RON activation induces the phosphorylation of Gab1, mitogen-activated protein kinase (MAPK), and protein kinase B (PKB) but not of signal transducer and activator of transcription 5 (Stat5). RON activation was sufficient to replace EPO in progenitor expansion but not in differentiation. In conclusion, we elucidated a novel mechanism specifically involved in the expansion of erythroblasts involving RON as a downstream target of the EpoR. (Blood. 2004;103:4457-4465)

SummarySensory circuits in the dorsal spinal cord integrate and transmit multiple cutaneous sensory modalities including the sense of light touch. Here, we identify a population of excitatory interneurons (INs) in the dorsal horn that are important for transmitting innocuous light touch sensation. These neurons express the ROR alpha (RORα) nuclear orphan receptor and are selectively innervated by cutaneous low threshold mechanoreceptors (LTMs). Targeted removal of RORα INs in the dorsal spinal cord leads to a marked reduction in behavioral responsiveness to light touch without affecting responses to noxious and itch stimuli. RORα IN-deficient mice also display a selective deficit in corrective foot movements. This phenotype, together with our demonstration that the RORα INs are innervated by corticospinal and vestibulospinal projection neurons, argues that the RORα INs direct corrective reflex movements by integrating touch information with descending motor commands from the cortex and cerebellum.

In the development of the mammalian intestine, Notch and Wnt/{beta}-catenin signals control stem cell maintenance and their differentiation into absorptive and secretory cells. Mechanisms that regulate differentiation of progenitors into the three secretory lineages, goblet, paneth, or enteroendocrine cells, are not fully understood. Using conditional mutagenesis in mice, we observed that Shp2-mediated MAPK signaling determines the choice between paneth and goblet cell fates and also affects stem cells, which express the leucine-rich repeat-containing receptor 5 (Lgr5). Ablation of the tyrosine phosphatase Shp2 in the intestinal epithelium reduced MAPK signaling and led to a reduction of goblet cells while promoting paneth cell development. Conversely, conditional mitogen-activated protein kinase kinase 1 (Mek1) activation rescued the Shp2 phenotype, promoted goblet cell and inhibited paneth cell generation. The Shp2 mutation also expanded Lgr5+ stem cell niches, which could be restricted by activated Mek1 signaling. Changes of Lgr5+ stem cell quantities were accompanied by alterations of paneth cells, indicating that Shp2/MAPK signaling might affect stem cell niches directly or via paneth cells. Remarkably, inhibition of MAPK signaling in intestinal organoids and cultured cells changed the relative abundance of Tcf4 isoforms and by this, promoted Wnt/{beta}-catenin activity. The data thus show that Shp2-mediated MAPK signaling controls the choice between goblet and paneth cell fates by regulating Wnt/{beta}-catenin activity.

Interneurons in the dorsal spinal cord process and relay innocuous and nociceptive somatosensory information from cutaneous receptors that sense touch, temperature and pain. These neurons display a well-defined organization with respect to their afferent innervation. Nociceptive afferents innervate lamina I and II, while cutaneous mechanosensory afferents primarily innervate sensory interneurons that are located in lamina III–IV. In this study, we outline a combinatorial transcription factor code that defines nine different inhibitory and excitatory interneuron populations in laminae III–IV of the postnatal cord. This transcription factor code reveals a high degree of molecular diversity in the neurons that make up laminae III–IV, and it lays the foundation for systematically analyzing and manipulating these different neuronal populations to assess their function. In addition, we find that many of the transcription factors that are expressed in the dorsal spinal cord at early postnatal times continue to be expressed in the adult, raising questions about their function in mature neurons and opening the door to their genetic manipulation in adult animals.

The tyrosine phosphatase Shp2 acts downstream of various growth factors, hormones or cytokine receptors. Mutations of the Shp2 gene are associated with several human diseases. Here we have ablated Shp2 in the developing kidneys of mice, using the ureteric bud epithelium-specific Hoxb7/Cre. Mutant mice produced a phenotype that is similar to mutations of the genes of the GDNF/Ret receptor system, that is: strongly reduced ureteric bud branching and downregulation of the Ret target genes Etv4 and Etv5. Shp2 mutant embryonic kidneys also displayed reduced cell proliferation at the branch tips and branching defects, which could not be overcome by GDNF in organ culture. We also examined compound mutants of Shp2 and Sprouty1, which is an inhibitor of receptor tyrosine kinase signaling in the kidney. Sprouty1 single mutants produce supernumerary ureteric buds, which branch excessively. Sprouty1 mutants rescued branching deficits in Ret−/− and GDNF−/− kidneys. Sprouty1; Shp2 double mutants showed no rescue of kidney branching. Our data thus indicate an intricate interplay of Shp2 and Sprouty1 in signaling downstream of receptor tyrosine kinases during kidney development. Apparently, Shp2 mediates not only GDNF/Ret but also signaling by other receptor tyrosine kinases in branching morphogenesis of the embryonic kidney.

Simple motor behaviors such as locomotion and respiration involve rhythmic and coordinated muscle movements that are generated by central pattern generator (CPG) networks in the spinal cord and hindbrain. These CPG networks produce measurable behavioral outputs, and thus represent ideal model systems for studying the operational principles that the nervous system uses to produce specific behaviors. Recent advances in our understanding of the transcriptional code that controls neuronal development have provided an entry point into identifying and targeting distinct neuronal populations that make up locomotor CPG networks in the spinal cord. This has spurred the development of new genetic approaches to dissect and manipulate neuronal networks both in the spinal cord and hindbrain. Here we discuss how the advent of molecular genetics together with anatomical and physiological methods has begun to revolutionize studies of the neuronal networks controlling rhythmic motor behaviors in mice.

Deregulation of signaling pathways, through mutation or other molecular changes, can ultimately result in disease. The tyrosine phosphatase Shp2 has emerged as a major regulator of receptor tyrosine kinase (RTK) and cytokine receptor signaling. In the last decade, germline mutations in the human PTPN11 gene, encoding Shp2, were linked to Noonan (NS) and LEOPARD syndromes, two multisymptomatic developmental disorders that are characterized by short stature, craniofacial defects, cardiac defects, and mental retardation. Somatic Shp2 mutations are also associated with several types of human malignancies, such as the most common juvenile leukemia, juvenile myelomonocytic leukemia (JMML). Whereas NS and JMML are caused by gain-of-function (GOF) mutations of Shp2, loss-of-function (LOF) mutations are thought to be associated with LEOPARD syndrome. Animal models that carry conditional LOF and GOF mutations have allowed a better understanding of the mechanism of Shp2 function in disease, and shed light on the role of Shp2 in signaling pathways that control decisive events during embryonic development or during cellular transformation/tumorigenesis.

The nonreceptor tyrosine phosphatase Shp2 (PTPN11) has been implicated in tyrosine kinase, cytokine, and integrin receptor signaling. We show here that conditional mutation of Shp2 in neural crest cells and in myelinating Schwann cells resulted in deficits in glial development that are remarkably similar to those observed in mice mutant for Neuregulin-1 (Nrg1) or the Nrg1 receptors, ErbB2 and ErbB3. In cultured Shp2 mutant Schwann cells, Nrg1-evoked cellular responses like proliferation and migration were virtually abolished, and Nrg1-dependent intracellular signaling was altered. Pharmacological inhibition of Src family kinases mimicked all cellular and biochemical effects of the Shp2 mutation, implicating Src as a primary Shp2 target during Nrg1 signaling. Together, our genetic and biochemical analyses demonstrate that Shp2 is an essential component in the transduction of Nrg1/ErbB signals.

Plakophilins are proteins of the armadillo family that function in embryonic development and in the adult, and when mutated can cause disease. We have ablated the plakophilin 2 gene in mice. The resulting mutant mice exhibit lethal alterations in heart morphogenesis and stability at mid-gestation (E10.5–E11), characterized by reduced trabeculation, disarrayed cytoskeleton, ruptures of cardiac walls, and blood leakage into the pericardiac cavity. In the absence of plakophilin 2, the cytoskeletal linker protein desmoplakin dissociates from the plaques of the adhering junctions that connect the cardiomyocytes and forms granular aggregates in the cytoplasm. By contrast, embryonic epithelia show normal junctions. Thus, we conclude that plakophilin 2 is important for the assembly of junctional proteins and represents an essential morphogenic factor and architectural component of the heart.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with fibrofatty replacement of cardiac myocytes, ventricular tachyarrhythmias and sudden cardiac death. In 32 of 120 unrelated individuals with ARVC, we identified heterozygous mutations in PKP2, which encodes plakophilin-2, an essential armadillo-repeat protein of the cardiac desmosome. In two kindreds with ARVC, disease was incompletely penetrant in most carriers of PKP2 mutations.

Metabolic activity of bacteria was investigated in open water, newly forming sea ice, and successive stages of pack ice in the Weddell Sea. Microautoradiography, using [(3)H]leucine as substrate, was compared with incorporation rates of [(3)H]leucine into proteins. Relation of [(3)H]leucine incorporation to the biomass of active bacteria provides information about changes of specific metabolic activity of cells. During a phytoplankton bloom in an ice-free, stratified water column, total numbers of bacteria in the euphotic zone averaged 2.3 × 10(5) ml(-1), but only about 13% showed activity via leucine uptake. Growth rate of the active bacteria was estimated as 0.3-0.4 days(-1). Total cell concentration of bacteria in 400 m depth was 6.6 × 10(4) ml(-1). Nearly 50% of these cells were active, although biomass production and specific growth rate were only about one-tenth that of the surface populations. When sea ice was forming in high concentrations of phytoplankton, bacterial biomass in the newly formed ice was 49.1 ng C ml(-1), exceeding that in open water by about one order of magnitude. Attachment of large bacteria to algal cells seems to cause their enrichment in the new ice, since specific bacterial activity was reduced during ice formation, and enrichment of bacteria was not observed when ice formed at low algal concentration. During growth of pack ice, biomass of bacteria increased within the brine channel system. Specific activity was still reduced at these later stages of ice development, and percentages of active cells were as low as 3-5%. In old, thick pack ice, bacterial activity was high and about 30% of cells were active. However, biomass-specific activity of bacteria remained significantly lower than that in open water. It is concluded that bacterial assemblages different to those of open water developed within the ice and were dominated by bacteria with lower average metabolic activity than those of ice-free water.