title: Endothelin-2 deficiency causes growth retardation, hypothermia, and emphysema in mice.
abstract: To explore the physiological functions of endothelin-2 (ET-2), we generated gene-targeted mouse models. Global Et2 knockout mice exhibited severe growth retardation and juvenile lethality. Despite normal milk intake, they suffered from internal starvation characterized by hypoglycemia, ketonemia, and increased levels of starvation-induced genes. Although ET-2 is abundantly expressed in the gastrointestinal tract, the intestine was morphologically and functionally normal. Moreover, intestinal epithelium-specific Et2 knockout mice showed no abnormalities in growth and survival. Global Et2 knockout mice were also profoundly hypothermic. Housing Et2 knockout mice in a warm environment significantly extended their median lifespan. However, neuron-specific Et2 knockout mice displayed a normal core body temperature. Low levels of Et2 mRNA were also detected in the lung, with transient increases soon after birth. The lungs of Et2 knockout mice showed emphysematous structural changes with an increase in total lung capacity, resulting in chronic hypoxemia, hypercapnia, and increased erythropoietin synthesis. Finally, systemically inducible ET-2 deficiency in neonatal and adult mice fully reproduced the phenotype previously observed in global Et2 knockout mice. Together, these findings reveal that ET-2 is critical for the growth and survival of postnatal mice and plays important roles in energy homeostasis, thermoregulation, and the maintenance of lung morphology and function.
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8584, USA.
authors.forename: Inik
authors.initials: I
authors.lastname: Chang
authors.forename: Alexa N
authors.initials: AN
authors.lastname: Bramall
authors.forename: Amy Greenstein
authors.initials: AG
authors.lastname: Baynash
authors.forename: Amir
authors.initials: A
authors.lastname: Rattner
authors.forename: Dinesh
authors.initials: D
authors.lastname: Rakheja
authors.forename: Martin
authors.initials: M
authors.lastname: Post
authors.forename: Stephen
authors.initials: S
authors.lastname: Joza
authors.forename: Colin
authors.initials: C
authors.lastname: McKerlie
authors.forename: Duncan J
authors.initials: DJ
authors.lastname: Stewart
authors.forename: Roderick R
authors.initials: RR
authors.lastname: McInnes
authors.forename: Masashi
authors.initials: M
authors.lastname: Yanagisawa
mesh_terms: D000818:Animals; D001786:Blood Glucose; D001833:Body Temperature Regulation / Q000235:genetics; D004041:Dietary Fats / Q000378:metabolism; D019333:Endothelin-2 / Q000172:deficiency* / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics; D015870:Gene Expression; D005804:Genes, Lethal; D006130:Growth Disorders / Q000235:genetics*; D007035:Hypothermia / Q000235:genetics*; D007408:Intestinal Absorption / Q000235:genetics; D007421:Intestine, Small / Q000378:metabolism / Q000503:physiopathology; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity; D011656:Pulmonary Emphysema / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D019333:Endothelin-2; D012333:RNA, Messenger