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PubMed1997

Absence of central cholinergic deficits in ApoE knockout mice.

ApolipoproteinE (ApoE) genotype has recently been identified as a major risk factor for Alzheimer's disease (AD) but the mechanism(s) by which ApoE isoforms influence this disease remain unclear. Recent studies suggest that mice deficient in ApoE may exhibit impaired central cholinergic function. Since this neurotransmitter system has traditionally been associated with the pathogenesis of AD, we have further investigated the impact of ApoE gene deletion on this system. Female ApoE knockout (ko) mice, age 12 months, were compared with wild type littermate controls using a range of behavioural, biochemical and histochemical techniques. Pre-treatment with the cholinomimetic, donepezil (E2020; 2.5-5 mg kg-1 IP), produced significant hypothermia and induction of tremor in both wild type and ApoE ko mice. The magnitude of change did not significantly differ between the groups. Cognitive testing in the Morris water maze revealed that both wild type and ApoE ko mice could learn the location of a hidden escape platform with similar rates of acquisition and accuracy. Similarly, the behaviour of both genotypes proved indistinguishable in a Y-maze spontaneous alteration procedure. The protocols used for both cognitive tests were then shown to be sensitive to the disruptive effects of scopolamine (but not scopolamine methyl bromide). Following behavioural testing, choline acetyltransferase (ChAT) activity was measured in the hippocampus, frontal and entorhinal cortex and striatum. In each case there was no difference between the genotypes. In addition, coronal sections of striatum and anterior hippocampal regions of ApoE ko and wild type mice showed similar patterns of acetylcholinesterase (AChE) staining, with no qualitative or obvious quantitative difference. Finally, analysis of plasma cholesterol levels confirmed ApoE genotype. In conclusion, using a combination of behavioural, histochemical and biochemical measurements, we have failed to detect any significant differences in central cholinergic activity between wild type and ApoE ko mice.

Acetylcholinesterase↗

PubMed2006

Bone biomechanical properties in EP4 knockout mice.

Among the four prostaglandin E receptor subtypes, EP(4) has been implicated as an important regulator of both bone formation and bone resorption; however, the integrated activities of this receptor on bone biomechanical properties have not been examined previously. This study compared the bone biomechanical properties of EP(4) knockout (KO) transgenic mice to strain-matched wild-type (WT) controls. We examined two groups of adult female mice: WT (n = 12) and EP(4) KO (n = 12). Femurs were tested in three-point bending and the lumbar-4 (L4) vertebral body by compression. Distal femur and vertebral body trabecular bone architecture were quantified using micro-computed tomography. Biomechanical structural parameters (ultimate/yield load, stiffness) were measured and apparent material parameters (ultimate/yield stress, modulus) calculated. Body weights and bone sizes were not different between EP(4) KO and WT mice (P > 0.05, Student's t-test). EP(4) KO mice exhibited reduced structural (ultimate/yield load) and apparent material (ultimate/yield stress) strength in the femoral shaft and vertebral body compared to WT (P < 0.05). Vertebral body stiffness and femoral neck ultimate load (structural strength) were marginally lower in EP(4) KO than that in WT mice (P < 0.1). In addition, EP(4) KO mice have smaller distal femur and vertebral bone volume to total volume (BV/TV) trabecular thickness than WT mice (P < 0.05). These results suggest that the prostaglandin receptor EP(4) has an important role in determining biomechanical competence in the mouse skeleton. Despite similar bone size, the absence of an EP(4) receptor may have removed a necessary link for bone adaptation pathways, which resulted in relatively weaker bone properties.

Animals↗

PubMed1999

Dental abnormalities associated with failure of tooth eruption in src knockout and op/op mice.

c-src knockout and op/op mice develop osteopetrosis as a result of defective osteoclast function and osteoclast formation, respectively. The mutant mice can be distinguished readily from their wild-type littermates around 10-12 days after birth because their incisors do not erupt, but the morphology of their teeth and surrounding bone has not been reported previously in detail. Histologic examination of jaws of src-mutant mice reveals unerupted, abnormal incisors within their bony crypts. The tooth roots are distorted by foci of haphazard proliferation of odontogenic epithelium associated with primitive tooth structures that strongly resemble the tumor-like lesions in humans, known as odontomas. The crowns of the incisors are fused to the adjacent bone, and the developing periodontal ligament is disordered and hypocellular. Osteoclasts are present in the bone surrounding the distorted teeth, but as in other bones in these mice they lack ruffled borders and thus do not resorb effectively. Similar odontogenic proliferation is present around unerupted incisors in op/op mice which form very few osteoclasts, but the amount is significantly less than in src mutant mice. Molars fail to erupt in both types of mutant mice, but they are not accompanied by aberrant odontogenic proliferation. These findings and previous reports of similar abnormalities in jaws from op/op rats suggest that failure of incisor eruption and associated proliferation of odontogenic epithelium in osteopetrotic rodents are a direct result of defective osteoclastic bone resorption.

Animals↗

PubMed2003

Impaired expression of an organic cation transporter, IMPT1, in a knockout mouse model for kidney stone disease.

The imprinted multimembrane-spanning polyspecific transporter-like gene 1 ( IMPT1) encodes a predicted protein with organic cation transport capabilities. As a first step in understanding the function of IMPT1, we identified the renal structures expressing this gene in knockout mice with adenine phosphoribosyltransferase (APRT) deficiency and 2,8-dihydroxyadenine (DHA) nephrolithiasis. IMPT1 mRNA was not detected using a standard in situ hybridization (ISH) protocol, but we observed intense staining in cortico-medullary tubules and glomeruli in wild-type mice using an improved reverse transcription-polymerase chain reaction (RT-PCR) ISH procedure. IMPT1 mRNA expression was significantly decreased in the cortical region in kidney sections from APRT-deficient male mice. APRT-deficient female mice are less severely affected by DHA-induced kidney stone disease, and we observed only a modest reduction in IMPT1 expression in kidneys from these mice. IMPT1 expression in APRT heterozygous mice was comparable to that in wild-type mice, suggesting imprinting of one of the parental alleles. These findings suggest that decreased IMPT1 mRNA expression may contribute to the impaired renal function in APRT-deficient male mice, and that RT-PCR ISH is a valuable tool for localizing the site of expression of transcripts that are not detectable using standard ISH procedures.

Adenine↗

PubMed2001

Early development of the gubernaculum and cremaster sac in estrogen receptor knockout mice.

AIM exogenous estrogen causes gubernacular atrophy and cryptorchidism in fetal rodents. Mice with an estrogen receptor-alpha (ERalpha) disrupted gene mutation (alphaERKO) were studied to determine whether ablation of endogenous estrogen action, through ERalpha, had an effect on gubernacular development. Serial sagittal sections were made of the pelvis in fetal and day 7 postnatal wild-type and alphaERKO mice with the estrogen receptor-alpha "knockout" gene mutation. Wild-type (n = 24), heterozygote (n = 13) and alphaERKO mice (n = 12) were sacrificed at 16, 17 and 18 days fetal life and at 7 days postnatally. The size of the gubernaculum, cremaster muscle, cremaster sac, and the width of the sac at both ends in day 7 mice were quantitated by computer analysis. Visually and statistically the ERKO mice could not be separated from the wild-type mice during fetal life. At day 7 postnatally, a thicker cremaster sac was noted morphologically, and also a statistically significant difference was seen in the width of the cremaster sac at the sac's tip. Sac area, cremaster muscle area and the width of the sac at the sac's end did not differ significantly. Overall there is minimal phenotypic change observed in the alphaERKO mouse compared to wild-type at the early developmental stages investigated. However, at postnatal day 7, there is a difference in the width of the cremasteric sac tip. This suggests that the effect of ERalpha, and thus signaling on the developing gubernaculum, occurs late in development. Alternatively, an action from the recently discovered ERbeta may be involved. Exploration of a betaERKO and the double knock-out alphaERKO/betaERKO mouse should be informative in evaluating the effect of endogenous estrogens in gubernacular development.

Animals↗

PubMed2002

Immunosenescence phenotypes in the telomerase knockout mouse.

Increasing generations of the telomerase knockout mouse, Terc-/-, show severe telomere dysfunction characterized by critically short telomeres and end-to-end chromosomal fusions. These mice also suffer from various age-related diseases affecting highly proliferative tissues. Among these pathologies are a reduced proliferative capacity of B and T cells, as well as a reduction of germinal center reactivity upon immunization. Both immune system defects are landmarks of immunosenescence. The study of the telomerase-deficient mouse model supports the notion that telomere shortening with age contributes to immunological dysfunction in the elderly.

Aging↗

PubMed1998

Pathological study of mice with total deficiency of sphingolipid activator proteins (SAP knockout mice).

Sphingolipid activator proteins (SAPs) A to D are lysosomal factors required in degradation of sphingolipids with short hydrophilic head groups and are derived from a precursor protein. Sap-B deficiency causes a variant of metachromatic leukodystrophy and sap-C deficiency causes a variant of Gaucher disease. Human total SAP deficiency has been reported in two patients in a single family. In these cases, various inclusions were described in the liver, skin, muscle and peripheral nerves ultrastructurally, but there was no report on the pathological study of the central nervous system (CNS). With targeted disruption of the precursor protein gene, we have generated mice with total SAP deficiency. These mice developed progressive neurological symptoms around day 20 and could not survive beyond day 40. Their cardinal pathology is extensive neurovisceral storage. Neuronal storage was already detected in the dorsal root ganglia as early as postnatal day 1 and diffuse neuronal storage was detected in the CNS after day 10. This storage was immunoreactive with anti-ubiquitin antibody and ultrastructurally appeared as inclusions consisting of numerous concentric lamellar and dense granular structures in the perikarya as well as in dendrites and axons. Axonal spheroids containing electron-dense concentric lamellar bodies and neurofilaments were also conspicuous. The extent of neuronal storage, numbers of storage neurons and axonal spheroids increased with age, accompanied with hypomyelination, astrogliosis and increase of macrophages. After day 30, argyrophilic tangle-like structures, which were immunoreactive with an antibody to phosphorylated neurofilaments, were found in the perikarya of many spinal and some neocortical neurons. Inclusions with various ultrastructural features were also noted in the glial cells, choroid plexus epithelial cells, vascular endothelial cells, Schwann cells, macrophages, fibroblasts, hepatocytes, and renal tubular epithelial cells. Some inclusions in the visceral organs were closely similar to those described in human cases of total SAP deficiency. The ultrastructural features of these inclusions in SAP knockout mice appeared unique and were different from those of other known sphingolipidoses.

Animals↗

PubMedDate not supplied

The effect of UV-B irradiation on primary and secondary HSV-1 infections in interleukin-4 knockout mice.

Ultraviolet B (UV-B) irradiation suppresses cell-mediated immunity and may lead to increased susceptibility to infectious diseases. Limited evidence suggests that exposure promotes a T helper (Th) 2 type of cytokine response with abrogation of a Th1 response. Several putative mediators of UV-induced immunosuppression have been identified, of which interleukin-4 (IL-4), an example of a Th2 cytokine, is one. Primary and secondary epidermal infections with herpes simplex virus (HSV) type 1 in IL-4 knockout (IL-4-/-) mice and the parent strain Bb 129 strain (IL-4+/+) were investigated using clinical features, phenotyping of cells from lymph nodes draining the sites of infection and lymphoproliferation assays. The IL-4-/- mice were more susceptible to both primary and secondary HSV infections than the parent mice. The percentage of lymph node dendritic cells (DC) expressing Ia was 45 in the IL-4+/+ mice but only 18 in the IL-4-/- strain, and the lymph node cells from infected IL-4-/- mice were less able to respond in vitro to HSV than those from the parent strain. Following suberythemal UV-B irradiation, more severe primary and secondary lesions resulted in both strains. There were fewer lymph node DC expressing Ia in both strains and this change was accompanied by suppression of the lymphoproliferation induced by HSV which was due to an effect on DC function rather than on the proliferative ability of the responding lymphocytes. UV-B exposure had no effect on ICAM-1 or B7.2 expression on the DC. Thus IL-4 seems to protect mice against HSV infection, and no evidence was obtained for the involvement of IL-4 in the UV-induced immunomodulation which results in more severe cutaneous HSV infections.

Animals↗

PubMed2001

Lysosomal sulfoglycolipid storage in the kidneys of mice deficient for arylsulfatase A (ASA) and of double-knockout mice deficient for ASA and galactosylceramide synthase.

The inherited deficiency of arylsulfatase A (ASA) causes lysosomal accumulation of sulfoglycolipids (mainly sulfo-galactosylceramide, S-GalCer ) and leads to metachromatic leukodystrophy in humans. Among visceral organs, kidneys are particularly affected. In the present study, the regional distribution and temporal development of sulfoglycolipid storage in kidneys of ASA-/- mice was investigated histochemically (alcian blue) and ultrastructurally. Furthermore, the sulfoglycolipid storage was examined in kidneys of double-knockout mice, which are incapable of: (a) degrading any sulfolipids (ASA-/-) and (b) synthesizing the major sulfolipid S-GalCer because of deficiency for galactosylceramide synthase (CGT), with the aim to search for additional ASA substrates. In ASA-/- mice, the nephron segments could be ranged in the order of decreasing sulfolipid storage: thin limbs of long-looped nephrons approximately thick ascending limbs > distal convoluted tubules > collecting ducts approximately short thin limbs. Macula densa and proximal tubules were unaffected. In ASA-/-/CGT-/- mice, the long thin limbs and distal convoluted tubules resembled those of ASA-/-/CGT+/+ mice, while the other segments showed less storage. The results suggest that the turnover of sulfolipids in general is highest in the distal nephron except macula densa, and that long thin limbs and distal convoluted tubules are the main sites for turnover of a minor sulfolipid species, which is known to be synthesized in the kidney of CGT-/- mice.

Animals↗

PubMed2002

Passive stiffness changes in soleus muscles from desmin knockout mice are not due to titin modifications.

Passive stiffness was found to be increased in mouse soleus muscles lacking desmin. Because titin is considered to be the major source of muscle elasticity, the stiffening might be explainable by titin adaptation. To test this, passive mechanical properties of single skinned fibres of soleus muscles from desmin knockout and control mice were analysed by using various extension tests. Titin expression was studied by SDS-gel electrophoresis. Absence of desmin did not modify either electrophoretic mobility of the titin band (3700 kDa) or optical density-unit ratios between bands for titin and nebulin (congruent with 0.3) and bands for titin and myosin heavy chain (congruent with 0.08). Elastic properties of fibres were not altered in the absence of desmin since passive tensions were similar under quasi-static (56-66 kN m(-2)) and dynamic (100-118 kN m(-2)) conditions whatever the kind of fibre. Thus, titin is unlikely to be responsible for the large increase in passive stiffness observed in whole soleus muscles when desmin is lacking.

Animals↗

PubMed2000

Substance P and central respiratory activity: a comparative in vitro study in NK1 receptor knockout and wild-type mice.

Neurokinin-1 receptors (NK1) are present within the respiratory medullary network and in the phrenic nucleus, which controls the diaphragm. We compared the efficacy of substance P (SP) at inducing changes in respiratory frequency or the amplitude of the respiratory motor output between NK1 knockout (NK1-/-) and wild-type mice, using the in vitro brainstem-spinal cord preparation. The in vitro respiratory frequency, as well as the variability of the rhythm and the amplitude of the motor output were similar in both lines. In wild-type mice, application of exogenous SP induced either an increase in respiratory frequency (superfusion of the medulla) or an increase of the inspiratory motor output, as defined by the integral of C4 cervical ventral root activity (superfusion of the spinal cord). These two effects were not apparent in NK1-/- mice. In conclusion, NK1 receptors mediate the respiratory responses to SP but the lack of NK1 receptors in newborn NK1-/- mice does not change the respiratory activity.

Action Potentials↗

PubMed2002

Tgfbeta2 -/- Tgfbeta3 -/- double knockout mice display severe midline fusion defects and early embryonic lethality.

Given all known biological activities, it is anticipated that transforming growth factors beta (TGF-betas) play important roles in many different developmental processes. As all three TGF-beta isoforms display overlapping expression patterns, deletion of one TGF-beta isoform might be compensated for by another. In the present study, targeted disruption of both Tgfbeta2 and Tgfbeta3 genes was undertaken to circumvent this problem and determine the essential roles of TGF-beta2 and TGF-beta3 in vivo. Tgfbeta2(-/-) Tgfbeta3(-/-) double knockout mice and their three-allelic Tgfbeta2(-/-) Tgfbeta3(+/-) littermates display a lack of distal parts of the rib, a lack of sternal primordia, and failure in ventral body wall closure, leading to an extrathoracic position of the heart and extrusion of the liver. In addition, abnormalities in connective tissue composition and an early embryonic lethality [around embryonic day (E) 15.5] are seen. In contrast, Tgfbeta2 (+/-) Tgfbeta3 (-/-) littermates show normal rib and sternum development, normal anterior body wall fusion, and are still alive on E18.5. TGF-beta2 is already known to play a role in skeletal and craniofacial development. The results presented here show that beyond this: (a). TGF-betas obviously play a fundamental role in midline fusion and (b). the Tgfbeta2 gene seems to play a more important role in mediating developmental processes than the Tgfbeta3 gene, since Tgfbeta2 (+/-) Tgfbeta3 (-/-) mutants - in contrast to their Tgfbeta2(-/-) Tgfbeta3 (+)(/-) littermates - do not display severe malformations.

Abnormalities, Multiple↗

PubMed1997

Eosinophilia and intracranial worm recovery in interleukin-5 transgenic and interleukin-5 receptor alpha chain-knockout mice infected with Angiostrongylus cantonensis.

We infected interleukin-5 (IL-5)-transgenic (IL-5-Tg) and IL-5 receptor alpha knockout (IL-5R alpha -/-) mice with Angiostrongylus cantonensis to determine the possible roles of IL-5 and eosinophils in A. cantonensis infection in mice. IL-5-Tg mice demonstrated significantly higher eosinophilia in bone marrow, blood and cerebrospinal fluid (CSF), lower intracranial worm recovery and smaller female worms than naive C3H/HeN mice. Both IL-5-Tg and C3H/HeN mice evoked antigen-specific serum and CSF IgA antibody responses as early as days 5 and 7 postinfection, respectively. Prominent eosinophil infiltration was noted around intracranial worms in the subarachnoid spaces of the mouse brains; eosinophils adhering to the worm surface were degranulated. In contrast, IL-5R alpha -/- mice yielded a higher worm recovery than wild-type or heterozygous mice at day 20 postinfection and failed to provoke CSF eosinophilia. These findings indicate that A. cantonensis infection in the mouse causes IL-5 production and subsequent CSF eosinophilia, the latter probably being involved in the killing of intracranial worms.

Angiostrongylus cantonensis↗

PubMed1999

Preimplantation diagnosis of the beta1 integrin knockout mutation as a model for aneuploid gene testing.

The autosomal beta1 integrin knockout mouse mutation was selected as a model to experimentally determine preimplantation diagnosis test reliability for autosomal gene deletions and duplications. In experiment 1, which analyzed 198 individually disaggregated single blastomeres, the observed test frequencies matched the mathematically predicted frequencies calculated from the independently derived values of 90% normal allele amplification, 92% mutant allele amplification, 4% alternate allele contamination, and 4% failure to transfer amplifiable target DNA into the PCR reaction mix. This experiment correctly predicted a normal embryonic phenotype in 143 (99.3%) of the 144 phenotypically normal autosomal recessive results. Experiment 2 compared single biopsied blastomere test results to test results on the remaining embryonic cells cultured 1 week until trophoblast outgrowth. Single biopsied blastomere analysis correctly predicted a normal autosomal recessive phenotype in 87 (98%) of the 89 embryos that would have been selected for implantation. Experiment 3 compared the PCR results of two biopsied blastomeres tested independently to the PCR result from the remaining cultured blastomeres to improve test reliability. Given that embryos would have been implanted only when two normal results were obtained, 17 of 17 phenotypically normal embryos would have been implanted from among the 44 embryos tested. These experiment 3 results are consistent with the mathematical prediction that about 99.9% of embryos implanted with two unaffected biopsied blastomere results would have had a phenotypically normal genotype.

Aneuploidy↗

PubMed2004

TNF/LTalpha double knockout mice display abnormal inflammatory and regenerative responses to acute and chronic liver injury.

Following acute liver injury, hepatocytes divide to facilitate regeneration. However, during chronic injury, hepatocyte proliferation is typically blocked and repair is mediated through liver progenitor (oval) cells. Signalling of the p55 tumour necrosis factor (TNF) receptor is central to these processes. Two ligands for p55 are known: TNF and lymphotoxin-alpha (LTalpha). However, one study suggests that another exists that mediates liver injury following viral challenge. We have therefore investigated whether ligands other than TNF and LTalpha are required for liver regeneration following either acute or chronic injury. Wild-type and double TNF/LTalpha knockout (TNF-/-LTalpha-/-) mice were subjected to either partial hepatectomy (PHx) or a choline-deficient ethionine-supplemented (CDE) diet. Proliferating hepatocytes, oval cells and inflammatory cells were identified and quantified in liver sections by immunohistochemistry. Liver inflammatory cells were characterised by cell surface antigen expression. Liver damage and mortality were monitored. Both hepatocyte and oval cell proliferation was reduced in TNF-/-LTalpha-/- mice. Lymphocyte clusters were evident in all TNF-/-LTalpha-/- livers and were heterogeneous, comprising B and T lymphocytes. PHx evoked liver inflammation in TNF-/-LTalpha-/- but not wild-type mice, whereas no difference was apparent between genotypes in CDE experiments. Thus, TNF/LTalpha signalling mediates liver regeneration involving both hepatocytes and progenitor cells. The hyper-inflammatory response following PHx in TNF-/-LTalpha-/- animals, which is absent following CDE-induced injury, demonstrates that the two forms of liver injury evoke discrete inflammatory responses and provides a model in which such differences can be examined further.

Acute Disease↗

PubMed2005

Expression of endothelial nitric oxide synthase is suppressed in the renal vasculature of angiotensinogen-gene knockout mice.

We have attempted to elucidate the mechanism by which endothelial-type nitric oxide synthase (eNOS) is regulated in the kidney, with special reference to the role of renal hemodynamics and angiotensin II (Ang II). We compared angiotensinogen gene knockout (Atg-/-) mice, which lacked Ang II (resulting in sodium/water depletion and severe hypotension), with wild-type (Atg+/+) mice. Using Western blot analysis and the NADPH diaphorase histochemical reaction, we found that the expression and activity of eNOS were markedly lower in the renal vessels of Atg-/- mice compared with wild-type (Atg+/+) mice. Dietary salt loading significantly enhanced renal eNOS levels and increased blood pressure in Atg-/- mice, but severe hypotension almost abolished the effects of salt loading. In contrast, in Atg+/+ mice, altered salt intake or hydralazine had no effect on renal eNOS levels. These results suggest that perfusion pressure plays an essential role in maintaining renal vascular eNOS activity, whereas Ang II plays a supportive role, especially when renal circulation is impaired.

Angiotensin II↗

PubMed2006

Adaptive changes in structure of skeletal muscles from adult Sod1 homozygous knockout mice.

Cu/Zn superoxide dismutase (SOD1), which is localized cytoplasmically and in the mitochondrial intermembrane space, is an enzyme that is critically important for superoxide free-radical elimination. Compared with age-matched wild-type littermates (Sod1 ( +/+ )), SOD1 homozygous knockout (Sod1 ( -/- )) mice have smaller body masses, heart and skeletal muscle masses, and muscle cross-sectional areas. At the light-microscopic level, cross sections of skeletal muscles from Sod1 ( -/- ) mice show no gross structural abnormalities. Following the staining of muscles of Sod1 ( -/- ) mice for succinate dehydrogenase (SDH) enzymatic activity, a grouping of SDH-positive fibers has been observed. Immunostaining for neural cell adhesion marker in the gastrocnemius muscle of Sod1 ( -/- ) mice has revealed a small number of atrophic denervated muscle fibers. No denervated fibers are observed in extensor digitorum longus (EDL), tibialis anterior, or plantaris muscles. An increase in mRNA expression levels of myogenin and acetylcholine receptor alpha has been detected in muscles in Sod1 ( -/- ) mice, but no changes in MyoD expression occur. Compared with fast oxidative fibers in EDL muscles of Sod1 ( +/+ ) mice, those of Sod1 ( -/- ) mice show increased accumulations of sub-sarcolemmal mitochondria. We conclude that the lack of SOD1 in adult Sod1 ( -/- ) mice does not result in extensive denervation of skeletal muscle fibers, although the distribution of fiber types is modified, and that fast oxidative fibers develop alterations in the amount and spatial distribution of sub-sarcolemmal mitochondria.

Adaptation, Physiological↗

PubMed2000

Pheochromocytoma cell lines from heterozygous neurofibromatosis knockout mice.

Transplantable tumors and cell lines have been developed from pheochromocytomas arising in mice with a heterozygous knockout mutation of the neurofibromatosis gene, Nf1. Nf1 encodes a ras-GTPase-activating protein, neurofibromin, and mouse pheochromocytoma (MPC) cells in primary cultures typically show extensive spontaneous neuronal differentiation that may result from the loss of the remaining wild-type allele and defective regulation of ras signaling. However, all MPC cell lines express neurofibromin, suggesting that preservation of the wild-type allele may be required to permit the propagation of MPC cells in vitro. MPC lines differ from PC12 cells in that they express both endogenous phenylethanolamine N-methyltransferase (PNMT) and full-length PNMT reporter constructs. PNMT expression is increased by dexamethasone and by cell-cell contact in suspension cultures. Mouse pheochromocytomas are a new tool for studying genes and signaling pathways that regulate cell growth and differentiation in adrenal medullary neoplasms and are a unique model for studying the regulation of PNMT expression.

Adrenal Gland Neoplasms↗