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R J Davis

Publications and source records attributed to R J Davis.

At least 37 records · Page 2Linked to original sources
PubMed2001

Characterization of mouse Dach2, a homologue of Drosophila dachshund.

The Drosophila genes eyeless, eyes absent, sine oculis and dachshund cooperate as components of a network to control retinal determination. Vertebrate homologues of these genes have been identified and implicated in the control of cell fate. We present the cloning and characterization of mouse Dach2, a homologue of dachshund. In situ hybridization studies demonstrate Dach2 expression in embryonic nervous tissues, sensory organs and limbs. This pattern is similar to mouse Dach1, suggesting a partially redundant role for these genes during development. In addition, we determine that Dach2 expression in the forebrain of Pax6 mutants and dermamyotome of Pax3 mutants is not detectably altered. Finally, genetic mapping experiments place mouse Dach2 on the X chromosome between Xist and Esx1. The identification of human DACH2 sequences at Xq21 suggests a possible role for this gene in Allan-Herndon syndrome, Miles-Carpenter syndrome, X-linked cleft palate and/or Megalocornea.

Amino Acid Sequence↗
PubMed2001

GADD45gamma mediates the activation of the p38 and JNK MAP kinase pathways and cytokine production in effector TH1 cells.

The p38 and JNK stress-activated MAPK signal transduction pathways are activated by T cell receptor (TCR) signaling and are required for IFN-gamma production by TH1 effector cells. Here, we show that the expression of GADD45gamma is induced during T cell activation and that the level of expression is higher in TH1 cells than in TH2 cells. TH1 cells from GADD45gamma(-/-) mice are severely compromised in their abilities to activate p38 and JNK in response to TCR signaling, produce much less IFN-gamma upon restimulation, and are deficient in activation-induced cell death (AICD). Additionally, GADD45gamma deficiencies caused reduced contact hypersensitivity in mice. Thus, GADD45gamma mediates activation of the p38 and JNK pathways and effector function of TH1 cells.

Animals↗
PubMed2001

Signaling by the JNK group of MAP kinases. c-jun N-terminal Kinase.

c-Jun N-terminal kinase (JNK) is one of the several main MAP kinase groups identified in mammals. Original studies by use of Jurkat T cells implicated JNK in T cell activation and interleukin (IL-2) expression. Recent advances using mouse genetic approaches have revealed novel functions of this pathway in primary mouse T cells. JNK is not essential for T-cell activation; instead, it is required for helper T differentiation into effector cells and their cytokine production. In this review, we summarize these advances in understanding the expression, function, and regulation of the JNK pathway in T-lymphocyte activation and differentiation.

Animals↗
PubMed2001

Spinal muscular atrophy disrupts the interaction of ZPR1 with the SMN protein.

The survival motor neurons (smn) gene in mice is essential for embryonic viability. In humans, mutation of the telomeric copy of the SMN1 gene causes spinal muscular atrophy, an autosomal recessive disease. Here we report that the SMN protein interacts with the zinc-finger protein ZPR1 and that these proteins colocalize in small subnuclear structures, including gems and Cajal bodies. SMN and ZPR1 redistribute from the cytoplasm to the nucleus in response to serum. This process is disrupted in cells from patients with Werdnig-Hoffman syndrome (spinal muscular atrophy type I) that have SMN1 mutations. Similarly, decreased ZPR1 expression prevents SMN localization to nuclear bodies. Our data show that ZPR1 is required for the localization of SMN in nuclear bodies.

Alternative Splicing↗
PubMed2001

Reproductive disease and congenital malformations caused by Menangle virus in pigs.

OBJECTIVE: To describe a new syndrome characterised by embryonic mortalities, stillbirths, mummified foetuses and congenital malformations in a herd of intensively farmed pigs. DESIGN: Field observations, laboratory investigations and examination of breeding records. PROCEDURE: Pathology examinations were performed on mummified and congenitally deformed piglets during an outbreak of reproductive disease at a 2600 sow intensive piggery in New South Wales from April to October 1997. Reproductive performance was monitored during the outbreak and breeding records were examined retrospectively. Serum and tissue samples from pigs were tested for evidence of infection with known porcine pathogens and for a new virus, Menangle virus, isolated from stillborn piglets with deformities from the affected piggery in August 1997. RESULTS: Reproductive disease occurred sequentially in all four breeding units at the affected piggery over a period of 21 weeks. The farrowing percentages in each unit decreased from 80 to 82% before the outbreak to 63 to 78% during the outbreak and the number of live piglets per litter declined from a mean of 9.6 to 9.8 before the outbreak to 7.2 to 8.9 during the outbreak. The proportion of affected litters (litters with less than six liveborn piglets) was highest (64%) in the sixth week of the outbreak. Mummified foetuses, stillborn piglets with arthrogryposis, craniofacial deformities and degeneration of the brain and spinal cord, were observed along with occasional abortions. Sera from sows that produced affected litters contained neutralising antibodies against Menangle virus and there was evidence that this virus had been introduced to the piggery in February 1997. CONCLUSIONS: Reproductive disease in pigs due to Menangle virus was characterised by stillbirths, mummification, embryonic death and infertility, along with abortions, skeletal deformities and degeneration of the brain and spinal cord in affected foetuses and stillborn piglets.

Animals↗
PubMed2001

Epidemiology and control of Menangle virus in pigs.

OBJECTIVE: To describe the epidemiology and eradication of Menangle virus infection in pigs. DESIGN: Field observations and interventions, structured and unstructured serological surveys, prospective and cross-sectional serological studies and laboratory investigations. PROCEDURE: Serum samples were collected from pigs at a 2600-sow intensive piggery in New South Wales that experienced an outbreak of reproductive disease in 1997. Serum samples were also collected from piggeries that received pigs from or supplied pigs to the affected piggery and from other piggeries in Australia. Serum and tissue samples were collected from pigs at piggeries experiencing reproductive disease in New South Wales. Sera and faeces were collected from grey-headed flying foxes (Pteropus poliocephalus) in the region of the affected piggery. Serum samples were tested for neutralising antibodies against Menangle virus. Virus isolation was attempted from faeces. RESULTS: Following the outbreak of reproductive disease, sera from 96% of adult pigs at the affected piggery, including sows that produced affected litters, contained neutralising antibodies against Menangle virus. Neutralising antibodies were also detected in sera from 88% of finisher pigs at two piggeries receiving weaned pigs from the affected piggery. No evidence of Menangle virus infection was found in other piggeries in Australia. In cross-sectional studies at the affected piggery, colostral antibodies were undetectable in most pigs by 14 to 15 weeks of age. By slaughter age or entry to the breeding herd, 95% of pigs developed high antibody titres (> or = 128) against Menangle virus in the virus neutralisation test. Menangle virus was eradicated from the affected piggery following a program of serological testing and segregation. Neutralising antibodies against Menangle virus were also detected in P poliocephalus from two colonies in the vicinity of the affected piggery. Two piggery workers were infected with Menangle virus. There was no evidence of infection in cattle, sheep, birds, rodents, feral cats and a dog at the affected piggery. CONCLUSIONS: Serological evidence of infection with Menangle virus was detected in pigs at a piggery that had experienced reproductive disease, in pigs at two associated piggeries and in fruit bats in the region of the piggery. Two humans were infected. The mode of transmission between pigs is unknown, but spread by faecal or urinary excretion is postulated. This virus can be eradicated by the segregation of pigs into discrete age groups.

Animals↗
PubMed2001

Dach1 mutant mice bear no gross abnormalities in eye, limb, and brain development and exhibit postnatal lethality.

Drosophila dachshund is necessary and sufficient for compound eye development and is required for normal leg and brain development. A mouse homologue of dachshund, Dach1, is expressed in the developing retina and limbs, suggesting functional conservation of this gene. We have generated a loss-of-function mutation in Dach1 that results in the abrogation of the wild-type RNA and protein expression pattern in embryos. Homozygous mutants survive to birth but exhibit postnatal lethality associated with a failure to suckle, cyanosis, and respiratory distress. The heart, lungs, kidneys, liver, and skeleton were examined to identify factors involved in postnatal lethality, but these organs appeared to be normal. In addition, blood chemistry tests failed to reveal differences that might explain the lethal phenotype. Gross examination and histological analyses of newborn eyes, limbs, and brains revealed no detectable abnormalities. Since Dach1 mutants die shortly after birth, it remains possible that Dach1 is required for postnatal development of these structures. Alternatively, an additional Dach homologue may functionally compensate for Dach1 loss of function.

Alleles↗
PubMed2001

Control of tumor size and disease activity during cotreatment with octreotide and the growth hormone receptor antagonist pegvisomant in an acromegalic patient.

We describe the case of an acromegalic subject, who was the first patient ever treated with the GH receptor antagonist pegvisomant. Furthermore, in this particular patient, progression in tumor size was encountered during treatment with pegvisomant. The patient described did benefit from cotreatment with pegvisomant and octreotide, including decreased GH levels, normalization of serum insulin-like growth factor I concentrations, and improvement of visual field defects.

Acromegaly↗
PubMed2000

Growth regulation via p38 mitogen-activated protein kinase in developing liver.

During normal development in the rat, hepatocytes undergo marked changes in the rate of proliferation. We have previously observed transient G(1) growth arrest at term, re-activation of proliferation immediately after birth, and a gradual transition to the quiescent adult hepatocyte phenotype after postnatal day 4. We hypothesized that these changes in proliferation are due in part to growth inhibitory effects mediated by the p38 mitogen-activated protein kinase pathway. p38 kinase activity measurements showed an inverse relationship with hepatocyte proliferation during the perinatal and postnatal transitions, whereas p38 content remained constant. Anisomycin activated the p38 pathway in fetal hepatocyte cultures while inducing growth inhibition that was sensitive to the p38 inhibitor, SB203580. Activation of p38 in these cultures, via transient transfection with a constitutively active form of its upstream kinase MKK6, also inhibited DNA synthesis as well as reducing cyclin D1 content. Transfection with inactive MKK6 did neither. Furthermore, MKK6-induced growth arrest was sensitive to SB203580. Finally, administration of SB203580 to near-term fetal rats in utero abrogated the transient hepatocyte growth arrest that occurs at term. These findings indicate a role for the p38 mitogen-activated protein kinase pathway in the physiological regulation of hepatocyte proliferation during normal development in the rat.

Aging↗
PubMed2000

Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3.

beta-Arrestins, originally discovered in the context of heterotrimeric guanine nucleotide binding protein-coupled receptor (GPCR) desensitization, also function in internalization and signaling of these receptors. We identified c-Jun amino-terminal kinase 3 (JNK3) as a binding partner of beta-arrestin 2 using a yeast two-hybrid screen and by coimmunoprecipitation from mouse brain extracts or cotransfected COS-7 cells. The upstream JNK activators apoptosis signal-regulating kinase 1 (ASK1) and mitogen-activated protein kinase (MAPK) kinase 4 were also found in complex with beta-arrestin 2. Cellular transfection of beta-arrestin 2 caused cytosolic retention of JNK3 and enhanced JNK3 phosphorylation stimulated by ASK1. Moreover, stimulation of the angiotensin II type 1A receptor activated JNK3 and triggered the colocalization of beta-arrestin 2 and active JNK3 to intracellular vesicles. Thus, beta-arrestin 2 acts as a scaffold protein, which brings the spatial distribution and activity of this MAPK module under the control of a GPCR.

Angiotensin II↗
PubMed2000

Dual roles for c-Jun N-terminal kinase in developmental and stress responses in cerebellar granule neurons.

c-Jun N-terminal kinases (JNKs) typically respond strongly to stress, are implicated in brain development, and are believed to mediate neuronal apoptosis. Surprisingly, however, JNK does not respond characteristically to stress in cultured cerebellar granule (CBG) neurons, a widely exploited CNS model for studies of death and development, despite the regulation of its substrate c-Jun. To understand this anomaly, we characterized JNK regulation in CBG neurons. We find that the specific activity of CBG JNK is elevated considerably above that from neuron-like cell lines (SH-SY5Y, PC12); however, similar elevated activities are found in brain extracts. This activity does not result from cellular stress because the stress-activated protein kinase p38 is not activated. We identify a minor stress-sensitive pool of JNK that translocates with mitogen-activated protein kinase kinase-4 (MKK4) into the nucleus. However, the major pool of total activity is cytoplasmic, residing largely in the neurites, suggesting a non-nuclear role for JNK in neurons. A third JNK pool is colocalized with MKK7 in the nucleus, and specific activities of both increase during neuritogenesis, nuclear JNK activity increasing 10-fold, whereas c-Jun expression and activity decrease. A role for JNK during differentiation is supported by modulation of neuritic architecture after expression of dominant inhibitory regulators of the JNK pathway. Channeling of JNK signaling away from c-Jun during differentiation is consistent with the presence in the nucleus of the JNK/MKK7 scaffold protein JNK-interacting protein, which inhibits JNK-c-Jun interaction. We propose a model in which distinct pools of JNK serve different functions, providing a basis for understanding multifunctional JNK signaling in differentiating neurons.

Animals↗
PubMed2000

JNK1 is required for T cell-mediated immunity against Leishmania major infection.

c-Jun N-terminal kinase (JNK) is a mitogen-activated protein kinase that plays important regulatory roles in helper T cell differentiation. In the current study, we used Jnk1-deficient mice to examine the function of JNK during an in vivo pathogenic infection, leishmaniasis, which is strongly influenced by Th1/Th2 effector mechanisms. The data show that Jnk1-deficient mice, despite their usually genetically resistant background, were unable to resolve Leishmania infections. Jnk1-/- mice displayed reduced delayed-type hypersensitivity in response to the pathogen, which was associated with a T cell defect. We found that, although these mice can direct an apparent Th1-response, there is also simultaneous generation of Leishmania-specific Th2 responses, which possibly down-modulate protective Th1-mediated immune function. These findings demonstrate that the negative regulation of Th2 cytokine production by the JNK1 signaling pathway is essential for generating Th1-polarized immunity against intracellular pathogens, such as Leishmania major.

Animals↗
PubMed2000

Role of the guanosine triphosphatase Rac2 in T helper 1 cell differentiation.

T helper 1 (TH1) cells mediate cellular immunity, whereas TH2 cells potentiate antiparasite and humoral immunity. We used a complementary DNA subtraction method, representational display analysis, to show that the small guanosine triphosphatase Rac2 is expressed selectively in murine TH1 cells. Rac induces the interferon-gamma (IFN-gamma) promoter through cooperative activation of the nuclear factor kappa B and p38 mitogen-activated protein kinase pathways. Tetracycline-regulated transgenic mice expressing constitutively active Rac2 in T cells exhibited enhanced IFN-gamma production. Dominant-negative Rac inhibited IFN-gamma production in murine T cells. Moreover, T cells from Rac2-/- mice showed decreased IFN-gamma production under TH1 conditions in vitro. Thus, Rac2 activates TH1-specific signaling and IFN-gamma gene expression.

Animals↗