Mouse model for bilateral adrenal hyperplasia.
Mouse model for bilateral adrenal hyperplasia.
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双侧肾上腺增生的小鼠模型。
DOI：
10.1016/j.ando.2009.02.004
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Martinez,A
中科院分区：
文献类型：
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作者：
Sahut-Barnola,I;DeJoussineau,C;Val,P;Lambert-Langlais,S;Lefrançois-Martinez,A-M;Pointud,J-C;Marceau,G;Sapin,V;Ragazzon,B;Bertherat,J;Kirschner,LS;Stratakis,CA;Martinez,A
原发性色素性结节性肾上腺皮质病（PPNAD）是一种罕见的双侧增生，由于垂体非依赖性皮质醇增多症和库欣综合征，导致高发病率。PPNAD可能是散发性的或被认为是Carney综合征（CNC）最常见的内分泌表现，CNC是一种以心脏粘液瘤、斑点状皮肤色素沉着和内分泌过度活动为特征的自体显性多发性肿瘤综合征[1]。分离的PPNAD和CNC均与PRKAR 1A的无效突变相关，PRKAR 1A是编码cAMP依赖性蛋白激酶（PKA）的1型α调节亚基（RI α）的基因[2和3]。在CNC患者和分离的PPNAD中观察到携带PRKAR 1A的染色体区域内的肿瘤特异性杂合性丢失，表明PRKAR 1A是潜在的肿瘤抑制基因[4]。由于Prkar 1a的一般纯合丢失在早期小鼠胚胎中是致命的[5]，因此需要肾上腺特异性敲除来证明肿瘤抑制活性。因此，我们通过将Prkar 1a floxed小鼠与Akr 1b 7-Cre小鼠系交配，产生了肾上腺皮质细胞中Prkar 1a基因失活的小鼠，Akr 1b 7-Cre小鼠系是我们开发的一种新型Cre表达系，允许肾上腺类固醇生成谱系中的特异性基因消融，而不影响性腺[6]。肾上腺皮质特异性Prkar 1a基因敲除小鼠（AdKO）发生垂体非依赖性库欣综合征和肾上腺皮质细胞分化和增殖失调的明显体征。这些缺陷导致胎儿肾上腺细胞在成人肾上腺中的不适当维持和扩增以及肿瘤前条件的建立。我们的数据提供了第一个体内证据，即PKA RI α亚基的缺失足以解释PPNAD中观察到的自主性肾上腺功能亢进和双侧增生。他们还强烈地表明，PKA活性失调对成年腺体中胎儿特征的维持有积极影响。
Primary pigmented nodular adrenocortical disease (PPNAD) is a rare form of bilateral hyperplasia leading to high morbidity due to pituitary-independent hypercortisolism and Cushing’s syndrome. PPNAD may be either sporadic or regarded as the most frequent endocrine manifestation of Carney’s complex (CNC), an autosomic dominant multiple neoplasia syndrome characterized by cardiac myxomas, spotty skin pigmentation and endocrine overactivity [1]. Both isolated PPNAD and CNC have been associated with null mutations in PRKAR1A, a gene encoding the type 1 α regulatory subunit (RI α) of the cAMP-dependent protein kinase (PKA)[2 and 3]. Tumor-specific loss of heterozygosity within the chromosomal region harboring PRKAR1A is observed in CNC patients and isolated PPNAD suggesting that PRKAR1A is a potential tumor suppressor gene [4]. Because general homozygous loss of Prkar1a is lethal in early mouse embryos [5], adrenal-specific knockout was required to demonstrate tumor suppressor activity. Therefore, we produced mice with Prkar1a gene inactivation in adrenocortical cells by mating Prkar1a floxed mice with the Akr1b7-Cre mouse line, a novel Cre expressing line we developed to allow specific gene ablation in the steroidogenic lineage of the adrenals without affecting the gonads [6]. Adrenal cortex-specific Prkar1a knockout mice (AdKO) develop pituitary-independent Cushing’s syndrome and evident signs of deregulated adrenocortical cells differentiation and proliferation. These defects lead to improper maintenance and expansion of foetal adrenal cells in adult adrenals and establishment of pretumoral conditions. Our data provide the first in vivo evidence that the absence of RI α subunit of PKA is sufficient to explain autonomous adrenal hyperactivity and bilateral hyperplasia observed in PPNAD. They also strongly suggest that deregulated PKA activity positively affects the maintenance of foetal characters in adult glands.