Mouse models for inherited endocrine and metabolic disorders

Abstract

In vivo models represent important resources for investigating the physiological mechanisms underlying endocrine and metabolic disorders, and for pre-clinical translational studies that may include the assessments of new treatments. In the study of endocrine diseases, which affect multiple organs, in vivo models provide specific advantages over in vitro models, which are limited to investigation of isolated systems. In recent years, the mouse has become the popular choice for developing such in vivo mammalian models, as it has a genome that shares w85% identity to that of man, and has many physiological systems that are similar to those in man. Moreover, methods have been developed to alter the expression of genes in the mouse, thereby generating models for human diseases, which may be due to loss-or gainof-function mutations. The methods used to generate mutations in the mouse genome include: chemical mutagenesis; conventional, conditional and inducible knockout models; knockin models and transgenic models, and these strategies are often complementary. This review describes some of the different strategies that are utilised for generating mouse models. In addition, some mouse models that have been successfully generated by these methods for some human hereditary endocrine and metabolic disorders are reviewed. In particular, the mouse models generated for parathyroid disorders, which include: the multiple endocrine neoplasias; hyperparathyroidism-jaw tumour syndrome; disorders of the calcium-sensing receptor and forms of inherited hypoparathyroidism are discussed. The advances that have been made in our understanding of the mechanisms of these human diseases by investigations of these mouse models are described.

GSK-3β Protein Phosphorylates and Stabilizes HLXB9 Protein in Insulinoma Cells to Form a Targetable Mechanism of Controlling Insulinoma Cell Proliferation

“…In mouse models, homozygous loss of Men1 in the insulinsecreting pancreatic islet ␤ cells or in the whole pancreas leads to only tumors of the ␤ cells (insulinoma) (4,5). Interestingly, Men1 loss in the islet ␣ cells causes insulinomas rather than glucagonomas because of trans-differentiation of menin-null ␣ cells into ␤ cells (6,7).…”

Endocrinology: Advances through omics and related technologies

“…Kang et al (2014) reviewed the strategies for genetic overexpression and knockout of specific genes in adipose tissues in order to better understand the role of adipose tissue in metabolic homeostasis in the context of different types of adipocytes. Another review (Piret and Thakker, 2011) described mouse models that have been generated for the study of human hereditary and metabolic disorders. McGonnell (2006) explored the use of genetically modified zebrafish as a novel and emerging model to study the endocrine system, often replacing the most commonly used mouse model.…”

“…McGonnell (2006) explored the use of genetically modified zebrafish as a novel and emerging model to study the endocrine system, often replacing the most commonly used mouse model. As these models have been extensively reviewed (Dungan Lemko and Elias, 2012;Kang et al, 2014;McGonnell, 2006;Piret and Thakker, 2011), here we will focus on a fish transgenic model, the growth hormone transgenic fish, as an example of the advances in the field and the potential applications of transgenic organisms.…”

Multiple Endocrine Neoplasia Type 1

“…Mice with germline homozygous loss of the Men1 gene ( Men1 –/–) die in utero between embryonic days 10.5 and 14.5 [11]. Approximately 30–40% of the embryos show delayed development with craniofacial abnormalities, defective neural tube closure, heart hypertrophy, abnormal liver organization, hemorrhages, and edemas [11]. Mice with germline heterozygous loss of the Men1 gene ( Men1 +/–) have been generated in four different laboratories (in Australia, France, UK and USA).…”

“…These mice gestate normally, but are tumor prone. After 9–16 months, they develop endocrine tumors similar to those in the human MEN1 syndrome: parathyroid tumors, pancreatic islet tumors (mainly insulinoma; also, glucagonoma, glucagon + insulin mixed-hormone tumors, or gastrinoma), anterior pituitary tumors (mainly prolactinoma; also, GH-secreting somatotropinoma), adrenal cortical tumors, thyroid tumors, gonadal tumors (Leydig cells in male, or ovarian stroma in female), mammary gland tumors, and lipomas [11]. Tumors in conventional Men1 +/− mice exhibit loss of the wild-type Men1 allele (LOH), thus supporting a tumor suppressor role of the Men1 gene in these tissues [11].…”