Hypoplasia of pancreatic islets in transgenic mice expressing activin receptor mutants.

Abstract

Activin, a member of the TGF-␤ superfamily, regulates the growth and differentiation of a variety of cell types. Based on the expression of activin in pancreatic rudiments of rat embryos and stimulation of insulin secretion from adult rat pancreatic islets by activin, activin is implicated in the development and function of islets. To examine the significance of activin signaling in the fetal and postnatal development of islets, transgenic mice expressing a dominant negative form of activin receptor (dn-ActR) or a constitutively active form of activin receptor (ActR-T206D) in islets were generated together with the transgenic mice expressing intact activin receptor (intact ActR) as a negative control. Transgenic mice with both dn-ActR and ActR-T206D showed lower survival rates, smaller islet area, and lower insulin content in the whole pancreas with impaired glucose tolerance when compared with transgenic mice with intact ActR or littermates, but they showed the same ␣ cell/ ␤ cell ratios as their littermates. In addition to islet hypoplasia, the insulin response to glucose was severely impaired in dnActR transgenic mice. It is suggested that a precisely regulated intensity of activin signaling is necessary for the normal development of islets at the stage before differentiation into ␣ and ␤ cells, and that activin plays a role in the postnatal functional maturation of islet ␤ cells. ( J. Clin. Invest. 1998. 102:294-301.)

Diabetes and pancreatic tumours in transgenic mice expressing Pa × 6

“…Mouse Pa 6 cDNA was a kind gift from Dr. P. Gruss (Max-Planck Institute for Biophysical Chemistry, Goettingen, Germany). For Insulin/Pa 6-Tg mice, mouse Pa 6 cDNA was inserted into the cloning site of the vector containing the insulin promoter (1.9 Kb) for transgenic mice [17]. From the lFIX II mouse 129SvJ genome library (Stratagene, La Jolla, Calif., USA), three independent clones containing the PDX1 promoter were obtained using the plaque screening method.…”

“…For immunohistochemistry, guinea-pig polyclonal antibodies against porcine insulin and glucagon (Dako, Kyoto, Japan) and a mouse monoclonal antibody (IgG2 a) against proliferating cell nuclear antigen (PCNA; Oncogene Science, Uniondale, N. Y., USA) were used. The quantitative analysis of islet-cell area was carried out as described previously [17]. In brief, islet area, alpha-cell area and beta-cell area were firstly identified with H&E staining, glucagon immunostaining and insulin immunostaining, respectively and secondly determined by superimposing microphotographs onto graph paper ruled into 1-mm squares.…”

“…The glucose tolerance test and the determination of blood glucose and serum insulin were carried out as described previously [17]. For the determi-nation of insulin content in the whole pancreas, each mouse pancreas was homogenized in 4 ml of ice-cold acid-ethanol solution (0.15 N HCl:75 % ethanol) [20], and insulin was extracted at 4°C overnight.…”

Genetic interactions between activin type IIB receptor and Smad2 genes in asymmetrical patterning of the thoracic organs and the development of pancreas islets

“…Although disruption of individual type II activin receptors results in nonoverlapping phenotypes, most of the phenotypes described for ActRIIA or ActRIIB mice exhibit incomplete penetrance and these two receptors show functional compensation during such patterning events. Type II activin receptors are broadly expressed in the mid-gestation mouse embryo, including in the pancreatic epithelium (Manova et al, 1995;Verschueren et al, 1995), and later are expressed in adult islets (Yamaoka et al, 1998). Pancreatic expression of a dominantnegative type II activin receptor in transgenic mice results in islet hypoplasia (Yamaoka et al, 1998;Shiozaki et al, 1999).…”

“…Type II activin receptors are broadly expressed in the mid-gestation mouse embryo, including in the pancreatic epithelium (Manova et al, 1995;Verschueren et al, 1995), and later are expressed in adult islets (Yamaoka et al, 1998). Pancreatic expression of a dominantnegative type II activin receptor in transgenic mice results in islet hypoplasia (Yamaoka et al, 1998;Shiozaki et al, 1999). The mice harboring null mutations in ActRIIA and ActRIIB such as ActRIIA ϩ/Ϫ ActRIIB ϩ/Ϫ and ActRIIB Ϫ/Ϫ exhibit hypoplastic pancreas islets and impaired glucose tolerance (Kim et al, 2000).…”