Loss of murine Na+/myo-inositol cotransporter leads to brain myo-inositol depletion and central apnea.
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(-/-) 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 [(3)H]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.
Berry
Gerard T
GT
Department of Pediatrics, University of Pennsylvania School of Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA. gerard.berry@jefferson.edu
Wu
Shuang
S
Buccafusca
Roberto
R
Ren
Jun
J
Gonzales
Linda W
LW
Ballard
Philip L
PL
Golden
Jeffrey A
JA
Stevens
Martin J
MJ
Greer
John J
JJ
D000483:Alleles; D000818:Animals; D001049:Apnea / Q000235:genetics*; D001921:Brain / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism; D004576:Electromyography; D004594:Electrophysiology; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D017353:Gene Deletion; D005838:Genotype; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D006720:Homozygote; D008168:Lung / Q000166:cytology / Q000473:pathology; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008957:Models, Genetic; D009474:Neurons / Q000378:metabolism; D016366:Open Reading Frames; D010641:Phenotype; D037662:Pulmonary Surfactant-Associated Protein A / Q000378:metabolism; D037701:Pulmonary Surfactant-Associated Protein B / Q000378:metabolism; D037721:Pulmonary Surfactant-Associated Protein C / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011995:Recombination, Genetic; D012964:Sodium / Q000494:pharmacology*; D013234:Stem Cells / Q000378:metabolism; D027981:Symporters / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D013997:Time Factors
D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D037662:Pulmonary Surfactant-Associated Protein A; D037701:Pulmonary Surfactant-Associated Protein B; D037721:Pulmonary Surfactant-Associated Protein C; D012333:RNA, Messenger; D027981:Symporters; C073884:SLC5A3 protein, human; D012964:Sodium