Influence of the Anx7 (+/-) knockout mutation and fasting stress on the genomics of the mouse adrenal gland.
The Anx7 gene codes for a Ca(2+)/GTPase with calcium channel and membrane fusion properties that has been proposed to regulate exocytotic secretion in chromaffin and other cell types. We have previously reported that the homozygous Anx7 (+/-) knockout mouse has an embryonically lethal phenotype. However, the viable heterozygous Anx7 (+/-) mouse displays a complex phenotype that includes adrenal gland hypertrophy, chromaffin cell hyperplasia, and defective IP(3) receptor (IP(3)R) expression. To search for a molecular basis for this phenotype, we have used cDNA microarray technology and have challenged control and mutant mice with fed or fasting conditions. We report that in the absence of the Anx7/IP(3)R signaling system, the cells in the adrenal gland are unable to discriminate between the fed and fasted states, in vivo. In control chromaffin cells, fasting is accompanied by an increased expression of structural genes for chromaffin cell contents, including chromogranin A and B, and DbetaH. There are also genes whose expression is specifically reduced. However, the Anx7 (+/-) mutation results in sustained expression of these nutritionally sensitive genes. We hypothesize that the calcium signaling defect due to the missing IP(3)R may be responsible for the global effects of the mutation on nutritionally sensitive genes. We further hypothesize that the tonically elevated expression of chromogranin A, a reportedly master control "switch" for dense core granule formation, may contribute to the process driving glandular hypertrophy and chromaffin cell hyperplasia in the Anx7 (+/-) mutant mouse.
Srivastava
Meera
M
Department of Anatomy, Physiology and Genetics, and Institute for Molecular Medicine, Uniformed Services University School of Medicine (USUHS), Bethesda, Maryland 20814, USA. msrivastava@usuhs.mil
Kumar
Preeti
P
Leighton
Ximena
X
Glasman
Mirta
M
Goping
Gertrude
G
Eidelman
Ofer
O
Pollard
Harvey B
HB
D000311:Adrenal Glands / Q000378:metabolism*; D000313:Adrenal Medulla / Q000378:metabolism; D000824:Animal Nutritional Physiological Phenomena; D000818:Animals; D017310:Annexin A7 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D015220:Calcium Channels / Q000378:metabolism; D019439:Chromaffin Cells / Q000378:metabolism; D053379:Chromogranin A; D002864:Chromogranins / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D019992:Databases as Topic; D005508:Food Deprivation; D006984:Hypertrophy; D053496:Inositol 1,4,5-Trisphosphate Receptors; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction
D017310:Annexin A7; D015220:Calcium Channels; D053379:Chromogranin A; D002864:Chromogranins; D018076:DNA, Complementary; D053496:Inositol 1,4,5-Trisphosphate Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear