Showing papers by "University of Texas Southwestern Medical Center published in 1996"
TL;DR: A review of the molecular basis of lymphocyte homing is presented, and mechanisms by which homing physiology regulates the homeostasis of immunologic resources are proposed.
Abstract: The integration and control of systemic immune responses depends on the regulated trafficking of lymphocytes. This lymphocyte "homing" process disperses the immunologic repertoire, directs lymphocyte subsets to the specialized microenvironments that control their differentiation and regulate their survival, and targets immune effector cells to sites of antigenic or microbial invasion. Recent advances reveal that the exquisite specificity of lymphocyte homing is determined by combinatorial "decision processes" involving multistep sequential engagement of adhesion and signaling receptors. These homing-related interactions are seamlessly integrated into the overall interaction of the lymphocyte with its environment and participate directly in the control of lymphocyte function, life-span, and population dynamics. In this article a review of the molecular basis of lymphocyte homing is presented, and mechanisms by which homing physiology regulated the homeostasis of immunologic resources are proposed.
2,925 citations
TL;DR: This revision supersedes the four previous updates in which a nomenclature system, based on divergent evolution of the P450 superfamily has been described and is similar to that proposed in the previous updates.
Abstract: We provide here a list of 481 P450 genes and 22 pseudogenes, plus all accession numbers that have been reported as of October 18,1995. These genes have been described in 85 eukaryote (including vertebrates, invertebrates, fungi, and plants) and 20 prokaryote species. Of 74 gene families so far descr
2,888 citations
TL;DR: It is shown that the class B scavenger receptor SR-BI is an HDL receptor, which mediates selective cholesterol uptake by a mechanism distinct from the classic LDL receptor pathway.
Abstract: High density lipoprotein (HDL) and low density lipoprotein (LDL) are cholesterol transport particles whose plasma concentrations are directly (LDL) and inversely (HDL) correlated with risk for atherosclerosis. LDL catabolism involves cellular uptake and degradation of the entire particle by a well-characterized receptor. HDL, in contrast, selectively delivers its cholesterol, but not protein, to cells by unknown receptors. Here it is shown that the class B scavenger receptor SR-BI is an HDL receptor. SR-BI binds HDL with high affinity, is expressed primarily in liver and nonplacental steroidogenic tissues, and mediates selective cholesterol uptake by a mechanism distinct from the classic LDL receptor pathway.
2,315 citations
TL;DR: Analysis of sensitivity to change in symptom severity in an open-label trial of fluoxetine showed that the IDs-C and IDS-SR were highly related to the 17-item Hamilton Rating Scale for Depression.
Abstract: The psychometric properties of the 28- and 30-item versions of the Inventory of Depressive Symptomatology, Clinician-Rated (IDS-C) and Self-Report (IDS-SR) are reported in a total of 434 (28-item) and 337 (30-item) adult out-patients with current major depressive disorder and 118 adult euthymic subjects (15 remitted depressed and 103 normal controls). Cronbach's alpha ranged from 0.92 to 0.94 for the total sample and from 0.76 to 0.82 for those with current depression. Item total correlations, as well as several tests of concurrent and discriminant validity are reported. Factor analysis revealed three dimensions (cognitive/mood, anxiety/arousal and vegetative) for each scale. Analysis of sensitivity to change in symptom severity in an open-label trial of fluoxetine (N = 58) showed that the IDS-C and IDS-SR were highly related to the 17-item Hamilton Rating Scale for Depression. Given the more complete item coverage, satisfactory psychometric properties, and high correlations with the above standard ratings, the 30-item IDS-C and IDS-SR can be used to evaluate depressive symptom severity. The availability of similar item content for clinician-rated and self-reported versions allows more direct evaluations of these two perspectives.
1,921 citations
TL;DR: It is shown that human cancer cell lines release a soluble factor or factors that dramatically affect DC maturation from precursors without affecting the function of relatively mature DCs, and one factor responsible for these effects was identified as vascular endothelial growth factor (VEGF).
Abstract: Inadequate presentation of tumor antigens by host professional antigen-presenting cells (APCs), including dendritic cells (DCs), is one potential mechanism for the escape of tumors from the host immune system. Here, we show that human cancer cell lines release a soluble factor or factors that dramatically affect DC maturation from precursors without affecting the function of relatively mature DCs. One factor responsible for these effects was identified as vascular endothelial growth factor (VEGF). Thus, VEGF may play a broader role in the pathogenesis of cancer than was previously thought, and therapeutic blockade of VEGF action may improve prospects for immunotherapy as well as inhibit tumor neovasculature.
1,863 citations
TL;DR: The results demonstrate the existence of a nuclear receptor signalling pathway for oxysterols and suggest that LXRα may be important as a sensor of cholesterol metabolites.
Abstract: Cholesterol and its oxysterol congeners are important constituents of cell membranes and function as intermediates in several crucial biosynthetic pathways. These compounds autoregulate their metabolic fate by end-product repression and activation of downstream catabolism. Although end-product repression by oxysterols is relatively well understood, the mechanism by which these compounds act as positive transcription signalling molecules is unknown. Here we identify a specific group of endogenous oxysterols that activate transcription through the nuclear receptor LXR alpha. Transactivation of LXR alpha by oxysterols occurs at concentrations at which these compounds exist in vivo. The most potent activators also serve as intermediary substrates in the rate-limiting steps of three important metabolic pathways: steroid hormone biosynthesis, bile acid synthesis, and conversion of lanosterol to cholesterol. Our results demonstrate the existence of a nuclear receptor signalling pathway for oxysterols and suggest that LXR alpha may be important as a sensor of cholesterol metabolites.
1,728 citations
TL;DR: Elucidation of the regulatory pathways involved in the repression of telomerase activity during development may lead to the ability to manipulate telomere levels and explore the consequences both for cellular aging and for the survival of cancer cells.
Abstract: Telomerase is a ribonucleoprotein that synthesizes telomere repeats onto chromosome ends and is involved in maintaining telomere length in germline tissues and in immortal and cancer cells. In the present study, the temporal regulation of expression of telomerase activity was examined in human germline and somatic tissues and cells during development. Telomerase activity was detected in fetal, newborn, and adult testes and ovaries, but not in mature spermatozoa or oocytes. Blastocysts expressed high levels of telomerase activity as did most human somatic tissues at 16-20 weeks of development with the exception of human brain tissue. This activity could no longer be detected in the somatic tissues examined from the neonatal period onward. Neither placenta nor cultured fetal amniocytes contained detectable telomerase activity. Fetal tissues explanted into primary cell culture showed a dramatic decline in telomerase activity which became undetectable after the first passage in vitro. Elucidation of the regulatory pathways involved in the repression of telomerase activity during development may lead to the ability to manipulate telomerase levels and explore the consequences both for cellular aging and for the survival of cancer cells.
1,387 citations
TL;DR: Tumor necrosis factor and lymphotoxin-α were isolated more than 10 years ago on the basis of their ability to kill tumor cells in vitro and to cause hemorrhagic necrosis of transplantable tumors in mice, and a factor known as cachectin was isolated from mouse macrophages, sequenced, and shown to be identical to TNF.
Abstract: Tumor necrosis factor (TNF) and lymphotoxin-α were isolated more than 10 years ago, on the basis of their ability to kill tumor cells in vitro and to cause hemorrhagic necrosis of transplantable tumors in mice.1 The complementary DNAs and genes encoding each protein were cloned immediately thereafter.2,3 Concurrently, a factor known as cachectin was isolated from mouse macrophages, sequenced, and shown to be identical to TNF.4,5 Cachectin was identified not as a cytolysin, but as a catabolic hormone that suppressed the expression of lipoprotein lipase and other anabolic enzymes in fat.6–8 Still other studies demonstrated the powerful . . .
1,248 citations
TL;DR: The discovery of new isoforms of mammalian adenylyl cyclase has revealed unanticipated mechanisms of regulation, including activation or inhibition by the G-protein beta gamma subunit complex, inhibition by G(o) alpha, inhibited by Ca2+, and phosphorylation by protein kinases C and A.
Abstract: Molecular cloning has permitted identification of several novel isoforms of mammalian adenylyl cyclase; these proteins now comprise a family of at least 10. All of the membrane-bound enzymes are activated by the alpha subunit of G alpha, a receptor-regulated, heterotrimeric guanine nucleotide-binding protein, and by the diterpene forskolin. Certain cyclases are also activated by Ca(2+)-calmodulin, while some are inhibited by the alpha subunits of the three Gi proteins. The discovery of new isoforms has also revealed unanticipated mechanisms of regulation, including activation or inhibition by the G-protein beta gamma subunit complex, inhibition by G(o) alpha, inhibition by Ca2+, and phosphorylation by protein kinases C and A. The effects of activators are often highly synergistic or conditional, suggesting function of these enyzmes as coincidence detectors. The plethora of receptors, G proteins, and adenylyl cyclases permits assembly of very complex signaling systems with a wide variety of integrative characteristics.
887 citations
TL;DR: It is indicated that the NH2-terminal domain of SREBP-1a can produce major effects on lipid synthesis and storage in the liver, owing to the engorgement of hepatocytes with cholesterol and triglycerides.
Abstract: The NH2-terminal domain of sterol-regulatory element binding protein-1a (SREBP-1a) activates transcription of genes encoding enzymes of cholesterol and fatty acid biosynthesis in cultured cells. This domain is synthesized as part of a membrane-bound precursor that is attached to the nuclear envelope and endoplasmic reticulum. In sterol-depleted cells a two-step proteolytic process releases this NH2-terminal domain, which enters the nucleus and activates transcription. Proteolysis is suppressed by sterols, thereby suppressing transcription. In the current experiments we produce transgenic mice that overexpress a truncated version of human SREBP-1a that includes the NH2-terminal domain but lacks the membrane attachment site. This protein enters the nucleus without a requirement for proteolysis, and therefore it cannot be down-regulated. Expression was driven by the phosphoenolpyruvate carboxykinase (PEPCK) promoter, which gives high level expression in liver. When placed on a low carbohydrate/high protein diet to induce the PEPCK promoter, the transgenic mice developed progressive and massive enlargement of the liver, owing to the engorgement of hepatocytes with cholesterol and triglycerides. The mRNAs encoding 3-hydroxy-3-methylglutaryl CoA (HMG CoA) synthase, HMG CoA reductase, squalene synthase, acetyl-CoA carboxylase, fatty acid synthase, and stearoyl-CoA desaturase-1 were all elevated markedly, as was the LDL receptor mRNA. The rates of cholesterol and fatty acid synthesis in liver were elevated 5- and 25-fold, respectively. Remarkably, plasma lipid levels were not elevated. The amount of white adipose tissue decreased progressively as the liver enlarged. These studies indicate that the NH2-terminal domain of SREBP-1a can produce major effects on lipid synthesis and storage in the liver.
817 citations
TL;DR: Localization to this microdomain is likely to optimize eNOS activation and the extracellular release of nitric oxide and that both myristoylation and palmitoylation are required to target the enzyme to caveolae and that each acylation process enhances targeting by 10-fold.
TL;DR: More than 80 models of prosthetic heart valves have been developed and used since the 1950s and more than 60,000 valve replacements are performed annually in the United States.
Abstract: Since the 1950s more than 80 models of prosthetic heart valves have been developed and used. More than 60,000 valve replacements are performed annually in the United States. Prosthetic heart valves may be mechanical or bioprosthetic. Mechanical valves, which are composed primarily of metal or carbon alloys, are classified according to their structure as caged-ball, single-tilting-disk, or bileaflet-tilting-disk valves. Bioprostheses may be heterografts, which are composed of porcine or bovine tissue (pericardial or valvular) mounted on a metal support, or homografts, which are preserved human aortic valves. The most commonly used prosthetic valves are listed in Table 1 and illustrated in Figure 1. . . .
TL;DR: This BRCA1–associated RING domain (BARD1) protein contains an N–terminal RING motif, three tandem ankyrin repeats, and a C-terminal sequence with significant homology to the phylogenetically conserved BRCT domains that lie near the C terminus of BRCa1.
Abstract: The hereditary breast and ovarian cancer gene, BRCA1, encodes a large polypeptide that contains the cysteine-rich RING motif, a zinc-binding domain found in a variety of regulatory proteins Here we describe a novel protein that interacts in vivo with the N-terminal region of BRCA1 This BRCA1-associated RING domain (BARD1) protein contains an N-terminal RING motif, three tandem ankyrin repeats, and a C-terminal sequence with significant homology to the phylogenetically conserved BRCT domains that lie near the C terminus of BRCA1 The BARD1/BRCA1 interaction is disrupted by BRCA1 missense mutations that segregate with breast cancer susceptibility, indicating that BARD1 may be involved in mediating tumour suppression by BRCA1
TL;DR: In this article, the authors compared the use of low-dose aspirin alone with heparin and lowdose aspirin in the treatment of the antiphospholipid antibody syndrome.
Journal Article•
TL;DR: In this paper, the authors used immunoblot analysis to determine whether eNOS is localized to plasmalemmal microdomains implicated in signal transduction called caveolae.
Abstract: Endothelial nitric-oxide synthase (eNOS) generates the key signaling molecule nitric oxide in response to intralumenal hormonal and mechanical stimuli We designed studies to determine whether eNOS is localized to plasmalemmal microdomains implicated in signal transduction called caveolae Using immunoblot analysis, eNOS protein was detected in caveolar membrane fractions isolated from endothelial cell plasma membranes by a newly developed detergent-free method; eNOS protein was not found in noneaveolar plasma membrane Similarly, NOS enzymatic activity was 94-fold enriched in caveolar membrane versus whole plasma membrane, whereas it was undetectable in non-caveolar plasma membrane 51-86% of total NOS activity in postnuclear supernatant was recovered in plasma membrane, and 57-100% of activity in plasma membrane was recovered in caveolae Immunoelectron microscopy showed that eNOS heavily decorated endothelial caveolae, whereas coated pits and smooth plasma membrane were devoid of gold particles Furthermore, eNOS was targeted to caveolae in COS-7 cells transfected with wild-type eNOS cDNA Studies with eNOS mutants revealed that both myristoylation and palmitoylation are required to target the enzyme to caveolae and that each acylation process enhances targeting by 10-fold Thus, acylation targets eNOS to plasmalemmal caveolae Localization to this microdomain is likely to optimize eNOS activation and the extracellular release of nitric oxide
TL;DR: Two RGS family members, GAIP and RGS4, are GTPase-activating proteins (GAPs), accelerating the rate of GTP hydrolysis by Gi alpha 1 at least 40-fold, consistent with their proposed role as negative regulators of G protein-mediated signaling.
TL;DR: Cardiac Na+,Ca2+ exchange is activated by a mechanism that requires hydrolysis of adenosine triphosphate but is not mediated by protein kinases, and PIP2 may be an important regulator of both ion transporters and channels.
Abstract: Cardiac Na+,Ca2+ exchange is activated by a mechanism that requires hydrolysis of adenosine triphosphate (ATP) but is not mediated by protein kinases. In giant cardiac membrane patches, ATP acted to generate phosphatidylinositol-4,5-bisphosphate (PIP2) from phosphatidylinositol (PI). The action of ATP was abolished by a PI-specific phospholipase C (PLC) and recovered after addition of exogenous PI; it was reversed by a PIP2-specific PLC; and it was mimicked by exogenous PIP2. High concentrations of free Ca2+ (5 to 20 microM) accelerated reversal of the ATP effect, and PLC activity in myocyte membranes was activated with a similar Ca2+ dependence. Aluminum reversed the ATP effect by binding with high affinity to PIP2. ATP-inhibited potassium channels (KATP) were also sensitive to PIP2, whereas Na+,K+ pumps and Na+ channels were not. Thus, PIP2 may be an important regulator of both ion transporters and channels.
TL;DR: Until substantially more is understood about cis-regulation over substantial regions of the genome it is prudent to consider these effects in design and in interpretation.
TL;DR: The epithelial/endothelial-stromal IL-1 system may mediate corneal tissue organization and responses to mechanical- and pathogen-induced injury through induction of keratocyte apoptosis and it is hypothesize that derangement's in this system may have a role in the pathogenesis of ker atoconus and other diseases of the cornea.
TL;DR: It is concluded that the primary systemic hemodynamic event, i.e., the postural decrease in stroke volume, was similar in finishers and nonfinishers and the heart rate response and cardiac output during standing were not significantly different, but thePostural vasoconstrictor response was significantly greater among the finishers.
Abstract: Orthostatic intolerance occurs commonly after spaceflight, and important aspects of the underlying mechanisms remain unclear. We studied 14 individuals supine and standing before and after three sp...
TL;DR: It is suggested that the scavenger receptor, class B, type I (SR-BI) mediates physiologically relevant uptake of cholesterol from HDL to nonplacental steroidogenic tissues in vivo.
Abstract: The scavenger receptor, class B, type I (SR-BI) binds HDL and mediates the selective transfer of cholesteryl esters from HDL to cultured cells. The tissue distribution of SR-BI in mice suggests that this receptor may deliver HDL-cholesterol to the liver and to nonplacental steroidogenic tissues. To examine the role of SR-BI in vivo, we determined its tissue and cell type-specific expression pattern and regulation in rats. High levels of immunodetectable SR-BI were present in the adrenal gland, ovary, and liver. In pregnant animals, the mammary gland also expressed high levels of the protein. SR-BI was localized by immunofluorescence to the surfaces of steroidogenic cells in the zona fasciculata and zona reticularis of the adrenal gland and to the corpus luteal cells of the ovary. High-dose estrogen treatment dramatically reduced SR-BI in the liver and increased SR-BI in the adrenal gland and corpus luteal cells of the ovary. These estrogen-induced increases in SR-BI in the adrenal gland and ovary were accompanied by enhanced in vivo uptake of fluorescent lipid from HDL. The administration of human chorionic gonadotropin induced a dramatic increase in SR-BI in the steroidogenic Leydig cells of the testes. These findings suggest that SR-BI mediates physiologically relevant uptake of cholesterol from HDL to nonplacental steroidogenic tissues in vivo.
TL;DR: CASK is a membrane-associated protein that combines domains found in Ca2+ - activated protein kinases and in proteins specific for intercellular junctions, suggesting that it may be a signaling molecule operating at the plasma membrane, possibly in conjunction with neurexins.
Abstract: Neurexins are neuronal cell surface proteins with hundreds of isoforms. In yeast two-hybrid screens for intracellular molecules interacting with different neurexins, we identified a single interacting protein called CASK. CASK is composed of an N-terminal Ca2+, calmodulin- dependent protein kinase sequence and a C-terminal region that is similar to the intercellular junction proteins dlg-A, PSD95/SAP90, SAP97, Z01, and Z02 and that contains DHR-, SH3-, and guanylate kinase domains. CASK is enriched in brain in synaptic plasma membranes but is also detectable at low levels in all tissues tested. The cytoplasmic domains of all three neurexins bind CASK in a salt-labile interaction. In neurexin I, this interaction is dependent on the C-terminal three residues. Thus, CASK is a membrane-associated protein that combines domains found in Ca2+ - activated protein kinases and in proteins specific for intercellular junctions, suggesting that it may be a signaling molecule operating at the plasma membrane, possibly in conjunction with neurexins.
TL;DR: It is shown that challenging cells that express the TM ligands Elk-L or Htk-L with the clustered ectodomain of Nuk induces phosphorylation of the ligands on tyrosine, a process that can be mimicked both in vitro and in vivo by an activated Src tyrosINE kinase.
Abstract: RECEPTOR tyrosine kinases of the EPH class have been implicated in the control of axon guidance and fascieulation1–7, in regulating cell migration8, and in defining compartments in the developing embryo9–11. Efficient activation of EPH receptors generally requires that their ligands be anchored to the cell surface, either through a transmembrane (TM) region or a glycosyl phosphatidylinositol (GPI) group12. These observations have suggested that EPH receptors can transduce signals initiated by direct cell–cell interaction. Genetic analysis of Nuk, a murine EPH receptor that binds TM ligands, has raised the possibility that these ligands might themselves have a signalling function6. Consistent with this, the three known TM ligands have a highly conserved cytoplasmic region, with multiple potential sites for tyrosine phosphorylation12–17. Here we show that challenging cells that express the TM ligands Elk-L or Htk-L with the clustered ectodomain of Nuk induces phosphorylation of the ligands on tyrosine, a process that can be mimicked both in vitro and in vivo by an activated Src tyrosine kinase. Co-culture of cells expressing a TM ligand with cells expressing Nuk leads to tyrosine phosphorylation of both the ligand and Nuk. These results suggest that the TM ligands are associated with a tyrosine kinase, and are inducibly phosphorylated upon binding Nuk, in a fashion reminiscent of cytokine receptors18. Furthermore, we show that TM ligands, as well as Nuk, are phosphorylated on tyrosine in mouse embryos, indicating that this is a physiological process. EPH receptors and their TM ligands therefore mediate bidirectional cell signalling.
TL;DR: The presence of aromatase expression in eutopic endometrial tissues from patients with endometriosis may be related to the capability of implantation of these tissues on peritoneal surfaces and the possibility of estrogen production in these implants may serve to promote their growth.
Abstract: The conversion of C19 steroids to estrogens occurs in a number of tissues, such as the ovary and placenta, and is catalyzed by aromatase P450 (P450arom; the product of the CYP19 gene). P450arom expression has also been detected in a number of uterine tumors, such as leiomyomas and endometrial cancer. On the other hand, P450arom expression was undetectable in normal endometrial and myometrial tissues. The present study was conducted to determine the presence or absence of aromatase expression in peritoneal endometriotic implants and in the eutopic endometrium of women with endometriosis. Endometriotic implants in pelvic peritoneum (n = 17; e.g. posterior culdesac, bladder, and anterior culdesac) and eutopic endometrial curettings (n = 11) of 14 patients with histologically documented pelvic endometriosis were obtained at the time of laparoscopy or laparotomy. Pelvic peritoneal biopsies distal to endometriotic implants as well as normal endometrial tissues (n = 7) from disease-free women were used as negative controls. We used competitive RT-PCR technology employing an internal standard to amplify P450arom transcripts in total ribonucleic acid (RNA) isolated from these tissues. P450arom transcripts were detected in all endometriotic implants and in all eutopic endometrial tissues from patients with endometriosis. P450arom messenger RNA species were not detectable in endometrial tissues from disease-free women or in endometriosis-free peritoneal tissues. The highest levels of transcripts were detected in an endometriotic implant that involved the full thickness of the anterior abdominal wall. The P450arom transcript level within the core of this endometriotic mass was 4-fold higher than that in the surrounding adipose tissue. It has been shown recently that aromatase expression in various human tissues is regulated by the use of tissue-specific promoters via alternative splicing. To analyze promoter usage, we amplified by RT-PCR the most likely promoter-specific untranslated 5'-termini of P450arom transcripts in 2 endometriotic implants. It appears that these endometriotic implants use both the adipose-type promoter I.4 and gonadal-type promoter II for aromatase expression. The use of promoter I.4 for aromatase expression in adipose tissue has been recently observed to be regulated by members of the interleukin-6 (IL-6) cytokine family. Based on these findings, we examined by RT-PCR, IL-6 and IL-11 messenger RNA expression in 5 endometriotic tissues and 1 eutopic endometrial sample from a patient with endometriosis. We detected IL-6 and IL-11 transcripts in all endometriotic tissues and in the eutopic endometrial tissue sample studied. Our findings indicate that both eutopic endometrial tissues and endometriotic implants from patients with endometriosis are biochemically different from normal endometrial tissues of disease-free women. The presence of aromatase expression in eutopic endometrial tissues from patients with endometriosis may be related to the capability of implantation of these tissues on peritoneal surfaces. Furthermore, the possibility of estrogen production in these implants may serve to promote their growth. Increased IL-6 and IL-11 expression in these tissues suggests that P450arom expression in endometriosis may be regulated in part by these cytokines.
TL;DR: Evidence caveolin is involved in transporting newly synthesized cholesterol from the ER directly to caveolae is presented and cholesterol transport to the cell surface was nearly 4 times more rapid in cells expressing caveolin than in matched cells lacking caveolin.
TL;DR: Using H-Ras-SREBP-2 fusion proteins, it is shown that the NH2-segment is released from membranes by two sequential cleavages and enters the nucleus and activates genes controlling cholesterol synthesis and uptake.
TL;DR: Heart formation requires complex interactions among cells from multiple embryonic origins that are conserved across vast phylogenetic distances, which has allowed cardiac development to be dissected in organisms ranging from flies to mammals.
Abstract: Heart formation requires complex interactions among cells from multiple embryonic origins. Recent studies have begun to reveal the genetic pathways that control cardiac morphogenesis. Many of the genes within these pathways are conserved across vast phylogenetic distances, which has allowed cardiac development to be dissected in organisms ranging from flies to mammals. Studies of cardiac development have also revealed the molecular defects underlying several congenital cardiac malformations in humans and may ultimately provide opportunities for genetic testing and intervention.
TL;DR: Sexual orientation and courtship behavior in Drosophila is regulated by fruitless (fru), the first gene in a branch of the sex-determination hierarchy functioning specifically in the central nervous system (CNS).
TL;DR: It is proposed that thegp330/megalin receptor is part of the maternal-fetal lipoprotein transport system and mediates the endocytic uptake of essential nutrients in the postgastrulation stage.
Abstract: gp330/megalin, a member of the low density lipoprotein (LDL) receptor gene family, is expressed on the apical surfaces of epithelial tissues, including the neuroepithelium, where it mediates the endocytic uptake of diverse macromolecules, such as cholesterol-carrying lipoproteins, proteases, and antiproteinases. Megalin knockout mice manifest abnormalities in epithelial tissues including lung and kidney that normally express the protein and they die perinatally from respiratory insufficiency. In brain, impaired proliferation of neuroepithelium produces a holoprosencephalic syndrome, characterized by lack of olfactory bulbs, forebrain fusion, and a common ventricular system. Similar syndromes in humans and animals are caused by insufficient supply of cholesterol during development. Because megalin can bind lipoproteins, we propose that the receptor is part of the maternal-fetal lipoprotein transport system and mediates the endocytic uptake of essential nutrients in the postgastrulation stage.
TL;DR: Lipton et al. as discussed by the authors identified Lyst, a candidate gene for Chediak-Higashi syndrome (CHS) and mutant beige (bg) mice, by direct complementary DNA selection from a yeast artificial chromosome (YAC) clone containing a 650-kilobase segment of the bg critical region on mouse chromosome 13.
Abstract: Vesicular transport to and from the lysosome and late endosome is defective in patients with Chediak-Higashi syndrome (CHS) and in mutant beige (bg) mice. CHS and bg cells have giant, perinuclear vesicles with characteristics of late endosomes and lysosomes that arise from dysregulated homotypic fusion. CHS and bg lysosomes also exhibit compartmental missorting of proteins, such as elastase, glucuronidase and cathepsin G. Lyst, a candidate gene for bg, was identified by direct complementary DNA selection from a yeast artificial chromosome (YAC) clone containing a 650-kilobase segment of the bg-critical region on mouse chromosome 13. Lyst is disrupted by a 5-kilobase deletion in bg mice, and Lyst messenger RNA is markedly reduced in bg homozygotes. The homologous human gene, LYST, is highly conserved with mouse Lyst, and contains a frame-shift mutation at nucleotides 117-118 of the coding domain in a CHS patient. Thus bg mice and human CHS patients have homologous disorders associated with Lyst mutations. Lyst encodes a protein with a carboxy-terminal prenylation motif and multiple potential phosphorylation sites. Lyst protein is predicted to form extended helical domains, and has a region of sequence similar to stathmin, a coiled-coil phosphoprotein thought to act as a relay integrating cellular signal response coupling.