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PubMed2001

Pathogenetic mechanisms of polycythemia vera and congenital polycythemic disorders.

The absolute polycythemias--those with increased red blood cell mass--can be divided into two groups: primary, caused by acquired or inherited mutations leading to a "gain-of-function" abnormalities expressed within the erythroid progenitors; and secondary, due to circulating serum factors, typically erythropoietin, stimulating erythropoiesis. This overview concentrates on the molecular biology of polycythemia vera (PV) discussed in the context of other polycythemic disorders. Recent advances in the regulation of erythropoiesis, as they may relate to polycythemic states, are discussed as a background for those well-defined polycythemic states wherein the molecular defect has not yet been elucidated. A number of cellular abnormalities associated with PV, including the hyperresponsiveness of PV progenitors to many cytokines as well as decreased expression of the thrombopoietin receptor on platelets and increased expression of Bcl-xL, suggest that the PV defect alters a number of cellular functions and is not restricted to cytokine receptor signal transduction. The increasing number of recognized instances of familial incidence of PV suggests that in these families the predisposition for PV is inherited as a dominant trait, and that PV is acquired as a new mutation that leads to a clonal hematopoiesis and may be due to loss of heterozygosity. The existence of these families provides a unique opportunity for isolation of the mutations in the gene leading to PV. Semin Hemaol 38(suppl 2):10-20.

Cytokines↗
PubMed2004

Pathology of a mouse mutation in peripheral myelin protein P0 is characteristic of a severe and early onset form of human Charcot-Marie-Tooth type 1B disorder.

Mutations in the gene of the peripheral myelin protein zero (P0) give rise to the peripheral neuropathies Charcot-Marie-Tooth type 1B disease (CMT1B), Déjérine-Sottas syndrome, and congenital hypomyelinating neuropathy. To investigate the pathomechanisms of a specific point mutation in the P0 gene, we generated two independent transgenic mouse lines expressing the pathogenic CMT1B missense mutation Ile106Leu (P0sub) under the control of the P0 promoter on a wild-type background. Both P0sub-transgenic mouse lines showed shivering and ultrastructural abnormalities including retarded myelination, onion bulb formation, and dysmyelination seen as aberrantly folded myelin sheaths and tomacula in all nerve fibers. Functionally, the mutation leads to dispersed compound muscle action potentials and severely reduced conduction velocities. Our observations support the view that the Ile106Leu mutation acts by a dominant-negative gain of function and that the P0sub-transgenic mouse represents an animal model for a severe, tomaculous form of CMT1B.

Action Potentials↗
PubMed2004

A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression.

Migraine is a common, disabling, multifactorial, episodic neurovascular disorder of unknown etiology. Familial hemiplegic migraine type 1 (FHM-1) is a Mendelian subtype of migraine with aura that is caused by missense mutations in the CACNA1A gene that encodes the alpha(1) subunit of neuronal Ca(v)2.1 Ca(2+) channels. We generated a knockin mouse model carrying the human pure FHM-1 R192Q mutation and found multiple gain-of-function effects. These include increased Ca(v)2.1 current density in cerebellar neurons, enhanced neurotransmission at the neuromuscular junction, and, in the intact animal, a reduced threshold and increased velocity of cortical spreading depression (CSD; the likely mechanism for the migraine aura). Our data show that the increased susceptibility for CSD and aura in migraine may be due to cortical hyperexcitability. The R192Q FHM-1 mouse is a promising animal model to study migraine mechanisms and treatments.

Animals↗
PubMed2006

Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms.

Mutations in human presenilin (PS) genes cause aggressive forms of familial Alzheimer's disease. Presenilins are polytopic proteins that harbour the catalytic site of the gamma-secretase complex and cleave many type I transmembrane proteins including beta-amyloid precursor protein (APP), Notch and syndecan 3. Contradictory results have been published concerning whether PS mutations cause 'abnormal' gain or (partial) loss of function of gamma-secretase. To avoid the possibility that wild-type PS confounds the interpretation of the results, we used presenilin-deficient cells to analyse the effects of different clinical mutations on APP, Notch, syndecan 3 and N-cadherin substrate processing, and on gamma-secretase complex formation. A loss in APP and Notch substrate processing at epsilon and S3 cleavage sites was observed with all presenilin mutants, whereas APP processing at the gamma site was affected in variable ways. PS1-Delta9 and PS1-L166P mutations caused a reduction in beta-amyloid peptide Abeta40 production whereas PS1-G384A mutant significantly increased Abeta42. Interestingly PS2, a close homologue of PS1, appeared to be a less efficient producer of Abeta than PS1. Finally, subtle differences in gamma-secretase complex assembly were observed. Overall, our results indicate that the different mutations in PS affect gamma-secretase structure or function in multiple ways.

Amyloid Precursor Protein Secretases↗
PubMed1999

Transformation-defective polyoma middle T antigen mutants defective in PLCgamma, PI-3, or src kinase activation enhance ERK2 activation and promote retinoic acid-induced, cell differentiation like wild-type middle T.

In HL-60 human myeloblastic leukemia cells, retinoic acid is known to cause cFMS, RAF, MEK, and ERK2 dependent myeloid cell differentiation and G0 arrest associated with RB tumor suppressor protein hypophosphorylation, implicating receptor tyrosine kinase signal transduction in propelling these retinoic acid-induced cellular effects. Furthermore, ectopic expression of polyoma middle T antigen, which activates similar early signal transduction molecules as PDGF class receptors such as cFMS, accelerates these retinoic acid-induced effects. To determine if this depends on middle T's ability to activate PLCgamma, PI-3 kinase, and src-like kinases, stable transfectants of HL-60 cells expressing either the polyoma middle T dl23 mutant, which is defective for PLCgamma and PI-3 kinase activation, or the Delta205 mutant, which in addition has greatly attenuated src-like kinase activation ability, were created and compared to wild-type middle T-transfected HL-60. The transgenes were under control of the retinoic acid (or 1, 25-dihydroxy vitamin D3) inducible Moloney murine leukemia virus LTRs. Expression of the dl23 or Delta205 mutant accelerated retinoic acid-induced cell differentiation. The effects of the mutants were comparable to those of the wild-type middle T. Likewise, retinoic acid-induced G0 arrest of mutant transfected cells and wild-type middle T transfected cells was similar. The same was true for 1, 25-dihydroxy vitamin D3-induced monocytic differentiation as for retinoic acid-induced myeloid differentiation. The mutants did not cause the same slight shortening of the cell cycle as wild-type middle T. Both the mutants and the wild-type middle T caused a similar increase in the cellular basal level of activated ERK2 MAPK. Since retinoic acid increases ERK2 activation, which is necessary for differentiation, the data suggest that mutant and wild-type middle T enhanced the retinoic acid effects by increasing basal levels of ERK2 activation. Consistent with this, the polyoma-induced foreshortening of the time for differentiation coincided with the time for retinoic acid to significantly increase ERK2 activation. As in wild-type HL-60, retinoic acid induced the early down-regulation of RXRalpha in mutant transfectants similar to wild-type middle T transfectants, consistent with no loss or gain of relevant functions due to the mutations. In contrast, vitamin D3 did not down-regulate RXRalpha in HL-60 or transfectants. Polyoma middle T and these transformation-defective mutants thus enhanced ERK2 activation to have an early effect in promoting retinoic acid-induced differentiation without a strong dependence on activating PLCgamma, PI-3 kinase, or src-like kinase.

Antigens, Viral, Tumor↗
PubMed1990

Fibrodysplasia ossificans progressiva: a clue from the fly?

Fibrodysplasia (myositis) ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by symmetrical congenital malformations of the blastemal anlage of the hands and feet and by progressive heterotopic chondrogenesis and ossification of the soft connective tissues. There is neither an established pathogenesis nor an effective treatment for this disabling disorder. We reevaluated the published data on the natural history of FOP and discovered an array of developmental gradients (characteristic patterns of disease expression) similar to developmental anomalies induced by pleiotropic mutations of the decapentaplegic (dpp) locus in Drosophila melanogaster. The protein encoded by the dpp locus is a member of the transforming growth factor-beta (TGF-beta) family of molecules. It shares 75% sequence homology with the c-terminal region of two recently cloned human bone morphogenetic proteins (BMP-2A, BMP-2B), also members of the TGF-beta family. The striking sequence identity across so large an evolutionary distance suggests that the BMP-2 genes in man and the dpp gene in the fly may be derived from a common ancestral gene. BMP is the only molecule discovered thus far that is capable of inducing endochondral ossification in vivo. Expression of endochondral bone formation is the basis for limb formation in embryogenesis, longitudinal bone growth in postnatal life, and local bone regeneration (fracture healing) following injury. We believe that FOP is a genetic disorder characterized by a disturbed developmental expression of this endochondral program and may represent a mutation resulting in a dominant gain of function. The developmental similarities between decapentaplegic in the fly and FOP in man suggest a useful model for the study of FOP. The use of such a model might be especially fruitful in suggesting a molecular basis for FOP.

Animals↗
PubMed2003

Transgenic and knock-out mice for deciphering the roles of EGFR ligands.

Generation of genetically engineered mice with either gain-of-function or loss-of-function mutations is the most popular technique for determining gene functions and the interrelationship between molecules in vivo. These models have provided a wealth of information about the developmental and physiological roles of oncogenes and growth factors. To date, transgenic techniques have been used extensively to study the functions of the epidermal growth factor (EGF) family. This review highlights some of the major recent findings pertinent to the EGF receptor (EGFR) and its ligands with special reference to elucidating how EGF and its related growth factors work together to regulate reproduction, growth and development. Finally, future investigations on ligand-ligand communications, EGFR and its ligands in neural stem cell research, and the mechanisms of EGFR signaling and trafficking in cells are also suggested.

Animals↗
PubMed2006

Inactive and active states and supramolecular organization of GPCRs: insights from computational modeling.

Herein we make an overview of the results of our computational experiments aimed at gaining insight into the molecular mechanisms of GPCR functioning either in their normal conditions or when hit by gain-of-function or loss-of-function mutations. Molecular simulations of a number of GPCRs in their wild type and mutated as well as free and ligand-bound forms were instrumental in inferring the structural features, which differentiate the mutation- and ligand-induced active from the inactive states. These features essentially reside in the interaction pattern of the E/DRY arginine and in the degree of solvent exposure of selected cytosolic domains. Indeed, the active states differ from the inactive ones in the weakening of the interactions made by the highly conserved arginine and in the increase in solvent accessibility of the cytosolic interface between helices 3 and 6. Where possible, the structural hallmarks of the active and inactive receptor states are translated into molecular descriptors useful for in silico functional screening of novel receptor mutants or ligands. Computational modeling of the supramolecular organization of GPCRs and their intracellular partners is the current challenge toward a deep understanding of their functioning mechanisms.

Animals↗
PubMed2005

Notch signaling controls proliferation through cell-autonomous and non-autonomous mechanisms in the Drosophila eye.

During Drosophila eye development, localized Notch signaling at the dorsal ventral (DV)-midline promotes growth of the entire eye field. This long-range action of Notch signaling may be mediated through the diffusible ligand of the Jak/STAT pathway, Unpaired (Upd), which was recently identified as a downstream target of Notch. However, Notch activity has not been shown to be cell-autonomously required for Upd expression and therefore yet another diffusible signal may be required for Notch activation of Upd. Our results clarify the Notch requirement, demonstrating that Notch activity at the DV-midline leads to cell-autonomous expression of Upd as monitored in loss and gain-of-function Notch clones. In addition, mutations in the Jak/STAT pathway interact genetically with the Notch pathway by suppressing Notch mediated overgrowth. N(act) clones show non-autonomous effects on the cell cycle anterior to the furrow, indicating function of the Jak/STAT pathway. However, cell-autonomous effects of Notch within and posterior to the furrow are independent of Upd. Here, Notch autonomously maintains cells in a proliferative state and blocks photoreceptor differentiation.

Animals↗
PubMed2006

Bmp and Wnt/beta-catenin signals control expression of the transcription factor Olig3 and the specification of spinal cord neurons.

In the developing spinal cord, signals of the roof plate pattern the dorsal progenitor domain and control the specification of three neuron types, dorsal interneurons dI1, dI2, and dI3. Bmp and Wnt/beta-catenin signals as well as transcription factors like Olig3 or Ngn1/2 are essential in this process. We have studied the epistatic relationship between Bmp and Wnt/beta-catenin signals and the transcription factor Olig3 in dorsal spinal cord patterning. Using beta-catenin gain-of-function and compound beta-catenin gain-of-function/Olig3 loss-of-function mutations in mice, we could show that Wnt/beta-catenin signals act upstream of Olig3 in the specification of dI2 and dI3 neurons. The analysis of such compound mutant mice allowed us to distinguish between the two functions of Wnt/beta-catenin signaling in proliferation and patterning of dorsal progenitors. Using electroporation of chick spinal cords, we further demonstrate that Bmp signals act upstream of Wnt/beta-catenin in the regulation of Olig3 and that Wnt/beta-catenin signals play an instructive role in controlling Olig3 expression. We conclude that Wnt/beta-catenin and BMP signals coordinately control the specification of dorsal neurons in the spinal cord.

Animals↗
PubMed1996

Carbohydrate recognition systems: functional triads in cell-cell interactions.

Considerable progress is being made in our understanding of the molecular basis for mammalian carbohydrate recognition systems. Selectins, related proteins and sialoadhesins are carbohydrate-binding proteins which serve as receptors in the orchestration of innate and acquired immune responses, inflammation and other forms of cell-cell communication. Protein structural studies and gain-of-function and loss-of-function mutations are providing clues to ways in which the receptors interact with monosaccharide elements of the oligosaccharide ligands. Binding experiments using oligosaccharides on lipid or protein carriers indicate that modes of presentation such as the clustered state and the manner of display on proteins are crucial factors determining whether a functional triad of receptor and ligand + carrier (counter-receptor) is formed.

Animals↗
PubMed2002

Membrane trafficking in Drosophila wing and eye development.

It is clear that membrane transport is essential to the proper sorting and delivery of membrane bound receptors and ligands, and secreted signaling molecules. Molecular genetic studies in Drosophila are particularly well suited to studies of membrane transport in development. The conservation of cell signaling pathways and membrane transport molecules between Drosophila and other species makes the results obtained in these studies of general interest. In addition, the ability to generate gain- and loss-of-function genetic mutations of various strengths, and the ability to generate transgenic flies that direct protein expression to tissues during development are of particular advantage. Several recent papers suggest that interesting and novel roles for membrane transport processes will be uncovered by studying classically defined membrane transport proteins in developmental contexts. Together these studies suggest that regulation of membrane transport may represent an additional mechanism to regulate the strength of cell-cell signaling during development.

Animals↗
PubMed2004

Neural crest cells: a model for invasive behavior.

Neural crest cells are the embryonic precursors of the neurons and glia of the peripheral nervous system, pigment cells, and connective tissue in the face, neck and heart. They are induced near the junction of the neural plate and embryonic ectoderm and undergo an epithelial to mesenchymal transition (EMT). Neural crest cells then display invasive behavior and migrate into the surrounding tissues along specific pathways. Neural crest cells are amenable to study in tissue culture, and the molecules that regulate their development can be studied in vivo with antisense techniques as well as with the expression of gain and loss-of-function constructs. Mutations in factors that regulate neural crest cell survival or differentiation can lead to cell death or the premature cessation of their migration, resulting in craniofacial abnormalities, pigmentation defects and the absence of enteric neurons. This paper reviews recent advances in our understanding of neural crest cell induction and migration, emphasizing both avian and amphibian models. Cell facts: The embryonic progenitors of pigment cells, the neurons and glia of the peripheral nervous system, as well as connective tissue in the face, neck and heart. Induced to form at the boundary of the neuroepithelium and embryonic ectoderm. Expression of the transcription factors Snail, Slug and FoxD3 leads to delamination from the neural tube. Invasive motility not unlike that of tumor cells can be studied in vitro. Express proteases, distinctive cell surface receptors and glycoproteins to acquire an invasive phenotype. Mutations of transcription factors expressed by the neural crest or in other factors that inhibit their premature differentiation can lead to survival and migration-associated birth defects.

Animals↗
PubMed1998

The oligomycin sensitivity conferring protein of rat liver mitochondrial ATP synthase: arginine 94 is important for the binding of OSCP to F1.

The oligomycin sensitivity conferring protein (OSCP) is an essential subunit of the mitochondrial ATP synthase (F0F1) long regarded as being directly involved in the energetic coupling of proton transport to ATP synthesis. To gain insight into the function of OSCP, mutations were made in a highly conserved central region of the subunit, and the recombinant proteins were studied using several biochemical assays. Rat liver OSCP was expressed to high levels in Escherichia coli, solubilized from inclusion bodies, renatured, and purified to homogeneity. The recombinant protein was able to reconstitute oligomycin-sensitive ATPase activity to inner membrane vesicles depleted of F1 and OSCP, and bound to F1 with a stoichiometry of 1:1. A novel fluorescence anisotropy assay was developed to study the affinity of binding of F1 to OSCP, providing a Kd value of 51 +/- 11 nM. Two highly conserved, charged residues (E91 and R94) which lie within the central region of OSCP were mutated, and the recombinant proteins (E91Q, R94Q, and R94A) were purified to homogeneity and judged by CD spectroscopy to have structures similar to that of the wild-type protein. Both R94 mutants demonstrated little or no binding to F1, while the E91Q bound in a manner identical to that of wild-type OSCP. Significantly, all three mutant proteins were able to reconstitute F1 with membranes and to confer oligomycin sensitivity to the same extent as wild-type OSCP. These results demonstrate that a single tight binding site exists on isolated rat liver F1 for OSCP, and implicate arginine 94 as playing a critical role in this site. In addition, these results indicate that this tight binding site is not required for conferral of oligomycin sensitivity to the reconstituted F0F1 complex.

Adenosine Triphosphatases↗
PubMed1995

Polyglutamine expansion as a pathological epitope in Huntington's disease and four dominant cerebellar ataxias.

A polyglutamine expansion (encoded by a CAG repeat) in specific proteins causes neurodegeneration in Huntington's disease (HD) and four other disorders, by an unknown mechanism thought to involve gain of function or toxicity of the mutated protein. The pathological threshold is 37-40 glutamines in three of these diseases, whereas the corresponding normal proteins contain polymorphic repeats of up to about 35 glutamines. The age of onset of clinical manifestations is inversely correlated to the length of the polyglutamine expansion. Here we report the characterization of a monoclonal antibody that selectively recognizes polyglutamine expansion in the proteins implicated in HD and in spinocerebellar ataxia (SCA) 1 and 3. The intensity of signal depends on the length of the polyglutamine expansion, and the antibody also detects specific pathological proteins expected to contain such expansion, in SCA2 and in autosomal dominant cerebellar ataxia with retinal degeneration, whose genes have not yet been identified.

Adult↗
PubMed2006

Delineation of the ADULT syndrome phenotype due to arginine 298 mutations of the p63 gene.

The ADULT syndrome (Acro-Dermato-Ungual-Lacrimal-Tooth, OMIM 103285) is a rare ectodermal dysplasia associated with limb malformations and caused by heterozygous mutations in p63. ADULT syndrome has clinical overlap with other p63 mutation syndromes, such as EEC (OMIM 604292), LMS (OMIM 603543), AEC (106260), RHS (129400) and SHFM4 (605289). ADULT syndrome characteristics are ectrodactyly, ectodermal dysplasia, mammary gland hypoplasia and normal lip and palate. The latter findings allow differentiation from EEC syndrome. LMS differs by milder ectodermal involvement. Here, we report three new unrelated ADULT syndrome families, all with mutations of arginine 298. On basis of 16 patients in five families with R298 mutation, we delineate the ADULT syndrome phenotype. In addition, we have documented a gain-of-function effect on the dNp63gamma isoform caused by this mutation. We discuss the possible relevance of oral squamous cell carcinoma in one patient, who carries this p63 germline mutation.

Abnormalities, Multiple↗
PubMed2002

Gastrointestinal stromal tumor: consistent CD117 immunostaining for diagnosis, and prognostic classification based on tumor size and MIB-1 grade.

Gain-of-function c-kit gene mutations and immunoreactivity of the c-kit protein CD117 in many gastrointestinal stromal tumors (GISTs) seem to support the idea that GISTs form a biologically distinct entity. In this study, the clinicopathologic features of 171 cases of GIST at a single institution were investigated for accurate diagnosis, and their relative risk for mortality was estimated by multivariate analysis. A GIST was defined diagnostically as a mesenchymal spindle or epithelioid cell lesion arising in the wall of the gastrointestinal tract with consistent immunoreactivity for CD117. The 171 patients with GISTs comprised 96 males (56.1%) and 75 females (43.9%), with a mean age of 59.4 years. One hundred and forty-five tumors (84.8%) occurred in the stomach, 18 (10.5%) in the small intestine, 6 (3.5%) in the rectum, and 2 (1.2%) in the esophagus. The median tumor size was 4.5 cm (range, 1.2 to 38 cm). Spindle-cell GISTs were present in 132 cases (77.2%); mixed GISTs, in 25 cases (14.6%); and epithelioid GISTs, in 14 cases (8.2%). Ten cases (55.6%) of spindled small intestine GIST contained eosinophilic skeinoid fibers. Immunoreactivity for CD34, h-caldesmon, alpha-smooth-muscle actin (SMA), desmin, and S-100 was observed in 156 (91.2%), 131 (76.6%), 46 (26.9%), 7 (4.1%), and 14 (8.2%) tumors, respectively. The percentage of CD34 positivity (38.8%) was low, in contrast with the high percentage of reactivity for SMA (77.8%) and S-100 (44.4%) in small intestine GISTs. By our histologic grading system using tumor differentiation, MIB-1 score, and necrosis, 129 tumors (75.4%) were classified as low grade and 42 tumors (24.6%) were classified as high grade. With a median follow-up period of 83.5 months for 122 living patients, the 5-year and 10-year survival rates were 81.7% and 67.4%, respectively. Multivariate analysis showed that both tumor size >10 cm and high grade were significantly associated with a poor outcome. As a result, GISTs >10 cm or high grade, 5 to 10 cm and low grade, and < or =5 cm and low grade were regarded as high risk, intermediate risk, and low risk for mortality, respectively. In conclusion, it is important to recognize GISTs that have a specific molecular pathogenesis and to separate them from other mesenchymal tumors with optimal immunostaining for CD117 when making a diagnosis and prognostic classification based on tumor size and MIB-1 grade.

Antigens, Nuclear↗