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Targeted Ablation of the Chromogranin A (Chga) Gene: Normal Neuroendocrine Dense-Core Secretory Granules and Increased Expression of Other Granins

Departments of Medicine (G.N.H., T.L., M.G., R.C.F., S.M., A.C.K., L.C.), Physiology (G.N.H., S.M.), Human Genetics (G.N.H., A.C.K.), Biochemistry (M.L.T.), and McGill Cancer Centre (M.L.T.), McGill University and Calcium Research Laboratory (G.N.H., L.C.), and Hormones and Cancer Research Unit (G.N.H.), Royal Victoria Hospital, Montreal, Québec, Canada H3A 1A1; and Département de Pharmacologie (R.De., R.Da.), Faculté de Médicine et Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Québec, Canada J1H 5N5

Address all correspondence and requests for reprints to: Dr. Geoffrey N. Hendy, Calcium Research Laboratory, Royal Victoria Hospital, 687 Pine Avenue West, Room H4.67, Montreal, Québec, Canada H3A 1A1. E-mail: geoffrey.hendy{at}mcgill.ca.

Chromogranin A (CgA), originally identified in adrenal chromaffin cells, is a member of the granin family of acidic secretory glycoproteins that are expressed in endocrine cells and neurons. CgA has been proposed to play multiple roles in the secretory process. Intracellularly, CgA may control secretory granule biogenesis and target neurotransmitters and peptide hormones to granules of the regulated pathway. Extracellularly, peptides formed as a result of proteolytic processing of CgA may regulate hormone secretion. To investigate the role of CgA in the whole animal, we created a mouse mutant null for the Chga gene. These mice are viable and fertile and have no obvious developmental abnormalities, and their neural and endocrine functions are not grossly impaired. Their adrenal glands were structurally unremarkable, and morphometric analyses of chromaffin cells showed vesicle size and number to be normal. However, the excretion of epinephrine, norepinephrine, and dopamine was significantly elevated in the Chga null mutants. Adrenal medullary mRNA and protein levels of other dense-core secretory granule proteins including chromogranin B, and secretogranins II to VI were up-regulated 2- to 3-fold in the Chga null mutant mice. Hence, the increased expression of the other granin family members is likely to compensate for the Chga deficiency.

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