Germline transmission in transgenic Huntington's disease monkeys

• Type of Material: Article
• Authors: Sean Moran, Emory University; Tim Chi, Emory University; Melinda S. Prucha, Emory University; Kwang Sung Ahn, Emory University; Fawn Connor-Stroud, Emory University; Sherrie Jean, Emory University; Kenneth Gould, Emory University; Anthony Chan, Emory University
• Language: English
• Date: 2015-07-15
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015 Elsevier Inc.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.theriogenology.2015.03.016
• Title of Journal or Parent Work: Theriogenology
• ISSN: 0093-691X
• Volume: 84
• Issue: 2
• Start Page: 277
• End Page: 285
• Grant/Funding Information: We also thank members of the Chan laboratory who provided assistance at the nursery and infant care. YNPRC is supported by the National Center for Research Resources P51RR165 and is currently supported by the Office of Research and Infrastructure Program (ORIP)/OD P51OD11132.; This study is supported by a grant awarded by the ORIP/NIH (RR018827) to AWSC.
• Keywords: Reproductive Biology; Ultrasound-guided intrauterine insemination; PLURIPOTENT STEM-CELLS; Transgenic Huntington's disease monkey; GENERATION; Life Sciences & Biomedicine; Veterinary Sciences; Germline transmission; CELLULAR PHENOTYPES; REPEAT INSTABILITY; NONHUMAN PRIMATE; ANIMAL-MODEL; Second generation; Science & Technology
• Research Categories: Biology, Neuroscience; Biology, Genetics; Biology, Cell

Abstract

Transgenic nonhuman primate models are an increasingly popular model for neurologic and neurodegenerative disease because their brain functions and neural anatomies closely resemble those of humans. Transgenic Huntington's disease monkeys (HD monkeys) developed clinical features similar to those seen in HD patients, making the monkeys suitable for a preclinical study of HD. However, until HD monkey colonies can be readily expanded, their use in preclinical studies will be limited. In the present study, we confirmed germline transmission of the mutant huntingtin (mHTT) transgene in both embryonic stem cells generated from three male HD monkey founders (F0) and in second-generation offspring (F1) produced via artificial insemination by using intrauterine insemination technique. A total of five offspring were produced from 15 females that were inseminated by intrauterine insemination using semen collected from the three HD founders (5 of 15, 33%). Thus far, sperm collected from the HD founder (rHD8) has led to two F1 transgenic HD monkeys with germline transmission rate at 100% (2 of 2). mHTT expression was confirmed by quantitative real-time polymerase chain reaction using skin fibroblasts from the F1 HD monkeys and induced pluripotent stem cells established from one of the F1 HD monkeys (rHD8-2). Here, we report the stable germline transmission and expression of the mHTT transgene in HD monkeys, which suggest possible expansion of HD monkey colonies for preclinical and biomedical research studies.