|
|
|
|||||||
|
|||||||||
J. Biol. Chem., Vol. 278, Issue 20, 18297-18302, May 16, 2003
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
From the Departments of myo-Inositol (Ins)
and its polyphosphoinositide derivatives that are important in membrane
signaling have long been held to play a special role in brain
metabolism. As polyphosphoinositides turn over rapidly and are
exceptionally abundant in nervous tissue, high Ins levels in the range
of 2-15 mM that have been observed in brain may be
necessary to maintain the rates of phosphoinositide synthesis in
diverse membrane locations within neurons. Cellular concentration
gradients of this magnitude indicate a dependence on active Ins
transport, especially at the time of growth and differentiation. The
Na+/myo-inositol cotransporter
(SMIT1 or SLC5A3) gene is highly expressed prenatally in the central nervous system and placenta. To gain more
insight into brain Ins metabolism, while ascertaining the importance of
SMIT1 as a transporter, we generated mice with a homozygous targeted
deletion of this gene. Newborn SMIT1(
Loss of Murine
Na+/myo-Inositol Cotransporter Leads
to Brain myo-Inositol Depletion and Central Apnea*
§,,,
,,, and Pediatrics and
** Pathology, University of Pennsylvania School of
Medicine, Divisions of Human Genetics and Molecular Biology and
Neonatology Research, The Children's Hospital of
Philadelphia, Philadelphia, Pennsylvania 19104, ¶ Department of
Physiology, Division of Neuroscience, University of Alberta, Edmonton,
Alberta T6G 2S2, Canada, and the Department
of Medicine, Division of Endocrinology and Metabolism, University of
Michigan Medical School, Ann Arbor, Michigan 48109-0354
/) animals
have no evidence of SMIT1 mRNA, a 92% reduction in the level of
brain Ins, an 84% reduction in whole body Ins, and expire shortly
after birth due to hypoventilation. Gross pathologic and light
microscopic examinations of each organ, as well as the placenta, of
embryonic day 18.5 fetuses at near term gestation were normal. Based on
[3H]acetate incorporation into phospholipids of lung
tissue explants, immunostaining of lung tissue for surfactant protein
A, B, and C, and electron microscopic examination of alveolar cells,
there was no evidence of abnormal pulmonary surfactant production by type 2 pneumocytes in lung. Although no histologic lesions were detected in the nervous system, electrophysiological studies of the
brainstem pre-Bötzinger respiratory control center demonstrated an abnormal rhythm discharge with periods of central apnea. The cause
of death can be explained by the regulatory defect in brainstem control
of ventilation. This model demonstrates the critical importance of
SMIT1 in the developing nervous system. The high affinity
SMIT1 transporter is responsible for the Ins concentration gradient in the murine fetal-placental unit.
*
This work was supported by grants from the March of Dimes
(to G. T. B.), the American Diabetes Association (to M. J. S.), and
the Canadian Institutes of Health (CIHR) (to J. J. G.). A preliminary
account of this work was initially reported, at least in part, at the
annual meeting of the American Society of Human Genetics in October
1999 in San Francisco, CA.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  J.-M. Beaulieu and M. G. Caron Looking at Lithium: Molecular Moods and Complex Behaviour Mol. Interv., October 1, 2008; 8(5): 230 - 241. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-L. Chen, S. Kauffman, and T. B. Reynolds Candida albicans Uses Multiple Mechanisms To Acquire the Essential Metabolite Inositol during Infection Infect. Immun., June 1, 2008; 76(6): 2793 - 2801. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Matrot, E. Durand, S. Dauger, G. Vardon, C. Gaultier, and J. Gallego Automatic classification of activity and apneas using whole body plethysmography in newborn mice J Appl Physiol, January 1, 2005; 98(1): 365 - 370. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. R. Chauvin and M. D. Griswold Characterization of the Expression and Regulation of Genes Necessary for myo-Inositol Biosynthesis and Transport in the Seminiferous Epithelium Biol Reprod, March 1, 2004; 70(3): 744 - 751. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Pagliardini, J. Ren, and J. J. Greer Ontogeny of the Pre-Botzinger Complex in Perinatal Rats J. Neurosci., October 22, 2003; 23(29): 9575 - 9584. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |