|ognizant Communication Corporation|
VOLUME 13, NUMBER 6
Gene Expression, Vol. 13, pp. 299-310
1052-2166/07 $90.00 + .00
Copyright © 2007 Cognizant Comm. Corp.
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When Half Is Not Enough: Gene Expression and Dosage in the 22q11 Deletion Syndrome
D. W. Meechan, T. M. Maynard, D. Gopalakrishna, Y. Wu, and A.-S. LaMantia
Department of Cell & Molecular Physiology, UNC Neuroscience Center, & Silvio M. Conte Center for Research in Mental Diseases, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA
The 22q11 Deletion Syndrome (22q11DS, also known as DiGeorge or Velo-Cardio-Facial Syndrome) has a variable constellation of phenotypes including life-threatening cardiac malformations, craniofacial, limb, and digit anomalies, a high incidence of learning, language, and behavioral disorders, and increased vulnerability for psychiatric diseases, including schizophrenia. There is still little clear understanding of how heterozygous microdeletion of approximately 30-50 genes on chromosome 22 leads to this diverse spectrum of phenotypes, especially in the brain. Three possibilities exist: 1) 22q11DS may reflect haploinsufficiency, homozygous loss of function, or heterozygous gain of function of a single gene within the deleted region; 2) 22q11DS may result from haploinsufficiency, homozygous loss of function, or heterozygous gain of function of a few genes in the deleted region acting at distinct phenotypically compromised sites; 3) 22q11DS may reflect combinatorial effects of reduced dosage of multiple genes acting in concert at all phenotypically compromised sites. Here, we consider evidence for each of these possibilities. Our review of the literature, as well as interpretation of work from our laboratory, favors the third possibility: 22q11DS reflects diminished expression of multiple 22q11 genes acting on common cellular processes during brain as well as heart, face, and limb development, and subsequently in the adolescent and adult brain.
Key words: 22q11 Deletion Syndrome (22q11DS); Phenotypes; Dosage; Gene expression
Address correspondence to Dr. Anthony LaMantia, Cell & Molecular Physiology (2442), University of North Carolina-Chapel Hill, 623 Coolidge Street, Chapel Hill, NC 27516-3005, USA. E-mail: Anthony_lamantia@med.unc.edu
Guarding the Blood-Brain Barrier: A Role for Estrogen in the Etiology of Neurodegenerative Disease
Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center College of Medicine, College Station, TX, USA
Although the effect of estrogen replacement therapy on the incidence of the neurodegenerative disease such as Alzheimer's disease is controversial, experimental studies indicate that estrogen replacement to young adult animals is neuroprotective and that perimenopausal estrogen replacement is associated with a decreased incidence of Alzheimer's disease. Estrogen affects a wide variety of cellular processes that can protect neuronal health. This article considers the disruption of the blood-brain barrier in Alzheimer's disease and forwards the hypothesis that estrogen may preserve neural health by maintaining the integrity of the blood-brain barrier.
Key words: Alzheimer's disease; Hormone therapy; Junction proteins; Endothelial cells; Cytokines
Address correspondence to Farida Sohrabji, Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, 228 Reynolds Medical Building, College Station, TX 77843, USA. Tel: 979-845-4072; Fax: 979-845-0790; E-mail: email@example.com
Expression Pattern for unc5b, an Axon Guidance Gene in Embryonic Zebrafish Development
Sukhbir Kaur,1 Mones S. Abu-Abab,2 Shobhit Singla,3 Sang-Yeob Yeo,4 and Ramani Ramchandran5
1Genome Technology Branch, NHGRI, National
Institutes of Health, Bethesda, MD, USA
2Laboratory of Pathology, NCI, National Institutes of Health, Bethesda, MD, USA
3Cornell University, Ithaca, NY, USA
4Laboratory of Molecular Genetics, Unit on Vertebrate Neural Development, NICHD, National Institutes of Health, Bethesda, MD, USA
5CRI Developmental Biology, Translational and Biomedical Research Center, Medical College of Wisconsin, Milwaukee, WI, USA
Branching processes such as nerves and vessels share molecular mechanisms of path determination. Our study focuses on unc5b, a member of the unc5 axon guidance gene family. Here, we have cloned the full-length zebrafish ortholog of unc5b, mapped its chromosome location in the zebrafish genome, and compared its expression patterns to robo4, another axon guidance family member. In situ show that unc5b is expressed predominantly in sensory structures such as the eye, ear, and brain. Both unc5b and robo4 show robust expression in all three compartments of the embryonic brain, namely forebrain, midbrain, and hindbrain. In particular, the hindbrain rhombomere expression displays interesting patterns in that robo4 is expressed in medial rhombomere cell clusters when compared to unc5b expressed in lateral rhombomere clusters. A similar medial-lateral theme is observed in other neural structures such as the neural tube. Our expression analysis provides a starting point for studying the role of axon guidance genes in embryonic hindbrain patterning.
Key words: unc5b; robo4; Hindbrain; Axon guidance; Zebrafish; Staining
Address correspondence to Ramani Ramchandran, CRI Developmental Biology, Translational and Biomedical Research Center, Medical College of Wisconsin, Department of Pediatrics, Developmental Vascular Biology Program, C3420, 8701 Watertown Plank Road, P.O. Box 26509, Milwaukee, WI 53226, USA. Tel: 414-955-2387; Fax: 414-955-6325; E-mail: firstname.lastname@example.org
Dominant-Negative Suppression of Big Brain Ion Channel Activity by Mutation of a Conserved Glutamate in the First Transmembrane Domain
Andrea J. Yool
Departments of Physiology, Pharmacology, and Cell Biology & Anatomy, the BIO5 Institute, and the Arizona Research Labs Division of Neurobiology, University of Arizona, Tucson, AZ 85724, USA
The neurogenic protein Drosophila big brain (BIB), which is involved in the process of neuroblast determination, and the water channel aquaporin-1 (AQP1) are among a subset of the major intrinsic protein (MIP) channels that have been found to show gated monovalent cation channel activity. A glutamate residue in the first transmembrane (M1) domain is conserved throughout the MIP family. Mutation of this residue to asparagine in BIB (E71N) knocks out ion channel activity, and when coexpressed with BIB wild-type as shown here generates a dominant-negative effect on ion channel function, measured in the Xenopus oocyte expression system using two-electrode voltage clamp. cRNAs for wild-type and mutant BIB or AQP1 channels were injected individually or as mixtures. The magnitude of the BIB ionic conductance response was greatly reduced by coexpression of the mutant E71N subunit, suggesting a dominant-negative mechanism of action. The analogous mutation in AQP1 (E17N) did not impair ion channel activation by cGMP, but did knock out water channel function, although not via a dominant-negative effect. This contrast in sensitivity between BIB and AQP1 to mutation of the M1 glutamate suggests the possibility of interesting structural differences in the molecular basis of the ion permeation between these two classes of channels. The dominant-negative construct of BIB could be a tool for testing a role for BIB ion channels during nervous system development in Drosophila.
Key words: Big brain (BIB); Aquaporin-1 (AQP1); Major intrinsic protein (MIP); Drosophila; Neuroblast; Cation channel
Address correspondence to Dr. Andrea Yool, P.O. Box 245051, Department of Physiology, University of Arizona, Tucson, AZ 85724, USA. Tel: 520-626-2198; Fax 520-626-2383; E-mail email@example.com
New address (as of August 2007): Discipline of Physiology, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia. E-mail: firstname.lastname@example.org
Gene Expression Analysis in Myotonic Dystrophy: Indications for a Common Molecular Pathogenic Pathway in DM1 and DM2
Annalisa Botta,1 Laura Vallo,1 Fabrizio Rinaldi,1 Emanuela Bonifazi,2 Francesca Amati,1 Michela Biancolella,1 Stefano Gambardella,1 Enzo Mancinelli,3 Corrado Angelini,4 Giovanni Meola,5 and Giuseppe Novelli1
1Department of Biopathology, Tor Vergata
University of Rome, Rome, Italy
2Tor Vergata Hospital, Medical Genetics Section, Rome, Italy
3Department of Biomolecular Sciences and Biotechnologies, University of Milan, Milan, Italy
4Department of Neurosciences, University of Padova, Padoa, Italy
5Department of Neurology, University of Milan, IRCCS San Donato Hospital, Milan Italy
An RNA gain-of-function of expanded transcripts is the most accredited molecular mechanism for myotonic dystrophy type 1 (DM1) and 2 (DM2). To disclose molecular parallels and divergences in pathogenesis of both disorders, we compared the expression profile of muscle biopsies from DM1 and DM2 patients to controls. DM muscle tissues showed a reduction in the major skeletal muscle chloride channel (CLCNl) and transcription factor Sp1 transcript levels and an abnormal processing of the CLCN1 and insulin receptor (IR) pre-mRNAs. No essential differences were observed in the muscle blind-like gene (MBNL1) and CUG binding protein 1 (CUGBP1) transcript levels as well as in the splicing pattern of the myotubularin-related 1 (MTMR1) gene. Macroarray analysis of 96 neuroscience-related genes revealed a considerable similar expression profile between the DM samples, reflective of a common muscle pathology origin. Using a twofold threshold, we found six misregulated genes important in calcium and potassium metabolism and in mitochondrial functions. Our results indicate that the DM1 and DM2 overlapping clinical phenotypes may derive from a common trans acting mechanism that traps and influences shared genes and proteins.
Key words: Myotonic dystrophy; Pathogenesis; Expression analysis; Splicing; Ion channels
Address correspondence to Annalisa Botta, Department
of Biopathology, Tor Vergata University of Rome, Via Montpellier, 100133
Rome, Italy. Tel: +39-6-72596078; Fax: +39-6-20427313; E-mail: email@example.com