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

Abstract

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.

Secretogranin III: a Bridge between Core Hormone Aggregates and the Secretory Granule Membrane

“…The intracellular quantity of dense core granules in adrenal chromaffin cells is somewhat controversial; some groups demonstrated a significant reduction of dense core granules [50,51], whereas another group reported that the dense core granules in the adrenal medulla are normal in both size and number [53]. Judging from the findings that Cga knockout mice exhibited no apparent defects in viability, fertility or neural/endocrine functions except abnormal leakage of catecholamines from the adrenal medulla, a single ablation of Cga or Cgb could be largely compensated for in most endocrine tissues/ cells by other granins [53]. The increased expression of the other granins in endocrine tissues of Cga- [50,53,54] and Cgb- [52] knockout mice supports the possibility of compensation.…”

“…Judging from the findings that Cga knockout mice exhibited no apparent defects in viability, fertility or neural/endocrine functions except abnormal leakage of catecholamines from the adrenal medulla, a single ablation of Cga or Cgb could be largely compensated for in most endocrine tissues/ cells by other granins [53]. The increased expression of the other granins in endocrine tissues of Cga- [50,53,54] and Cgb- [52] knockout mice supports the possibility of compensation.…”

The Crucial Role of Chromogranins in Storage and Exocytosis Revealed Using Chromaffin Cells from Chromogranin A Null Mouse

“…Previously, strains of mice with homozygous (Ϫ/Ϫ) targeted ablation [knock out (KO)] of the CgA locus have been developed (CgA-KO) (Mahapatra et al, 2005;Hendy et al, 2006). In this report, we used CgA-KO animals in combination with amperometry, patch amperometry, and intracellular electrochemical techniques to directly study, for the first time, the participation of intravesicular CgA in the storage and in the release process of CA from adrenal chromaffin cells.…”

Spatio-temporal expression of chromogranin A during zebrafish embryogenesis

“…The mutant null mice for the Chga were viable and fertile and had no obvious developmental abnormalities, and their neural and endocrine functions are not grossly impaired. The authors contribute this to the compensation of the other granin family members (Hendy et al 2006). Anyway, the specific expression of chga in zebrafish nervous system may give us clues to pay attention to relationship between the chga and nerve development.…”