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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Model of pediatric pituitary hormone deficiency separates the endocrine and neural functions of the LHX3 transcription factor in vivo
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Model of pediatric pituitary hormone deficiency separates the endocrine and neural functions of the LHX3 transcription factor in vivo

机译：小儿垂体激素缺乏症模型在体内分离LHX3转录因子的内分泌和神经功能

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摘要

The etiology of most pediatric hormone deficiency diseases is poorly understood. Children with combined pituitary hormone deficiency (CPHD) have insufficient levels of multiple anterior pituitary hormones causing short stature, metabolic disease, pubertal failure, and often have associated nervous system symptoms. Mutations in developmental regulatory genes required for the specification of the hormone-secreting cell types of the pituitary gland underlie severe forms of CPHD. To better understand these diseases, we have created a unique mouse model of CPHD with a targeted knockin mutation (Lhx3 W227ter), which is a model for the human LHX3 W224ter disease. The LHX3 gene encodes a LIM-homeodomain transcription factor, which has essential roles in pituitary and nervous system development in mammals. The introduced premature termination codon results in deletion of the carboxyl terminal region of the LHX3 protein, which is critical for pituitary gene activation. Mice that lack all LHX3 function do not survive beyond birth. By contrast, the homozygous Lhx3 W227ter mice survive, but display marked dwarfism, thyroid disease, and female infertility. Importantly, the Lhx3 W227ter mice have no apparent nervous system deficits. The Lhx3 W227ter mouse model provides a unique array of hormone deficits and facilitates experimental approaches that are not feasible with human patients. These experiments demonstrate that the carboxyl terminus of the LHX3 transcription factor is not required for viability. More broadly, this study reveals that the in vivo actions of a transcription factor in different tissues are molecularly separable.
机译：大多数儿童激素缺乏症的病因了解甚少。合并垂体激素缺乏症（CPHD）的儿童的垂体前叶多种激素水平不足，会导致身材矮小，代谢疾病，青春期衰竭，并经常伴有神经系统症状。规范脑垂体分泌激素的垂体激素类型所必需的发育调控基因突变。为了更好地了解这些疾病，我们创建了具有针对性敲入突变（Lhx3 W227ter）的CPHD独特小鼠模型，该模型是人类LHX3 W224ter疾病的模型。 LHX3基因编码一个LIM同源域转录因子，该因子在哺乳动物的垂体和神经系统发育中具有重要作用。引入的过早终止密码子导致LHX3蛋白羧基末端区域的缺失，这对垂体基因激活至关重要。缺乏所有LHX3功能的小鼠无法存活至出生。相比之下，纯合Lhx3 W227ter小鼠存活下来，但表现出明显的侏儒症，甲状腺疾病和女性不育症。重要的是，Lhx3 W227ter小鼠没有明显的神经系统缺陷。 Lhx3 W227ter小鼠模型提供了一系列独特的激素缺陷，并促进了人类患者不可行的实验方法。这些实验表明，LHX3转录因子的羧基末端不是生存力所必需的。更广泛地说，这项研究揭示了转录因子在不同组织中的体内作用在分子上是可分离的。

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    Stephanie C. Colvin; Raleigh E. Malik; Aaron D. Showalter; Kyle W. Sloop; Simon J. Rhodes;

  • 作者单位

    Departments of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN 46202,Department of Biology, Indiana University-Purdue University, Indianapolis, IN 46202;

    Departments of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN 46202,Departments of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202;

    Endocrine Discovery, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285;

    Endocrine Discovery, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285;

    Departments of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN 46202,Department of Biology, Indiana University-Purdue University, Indianapolis, IN 46202,Departments of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    endocrinology; growth; reproduction; metabolism;

    机译：内分泌学;生长;生殖;新陈代谢;

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