Embryonic Lethality in Homozygous Human Her-2 Transgenic Mice Due to Disruption of the Pds5b Gene.
The development of antigen-targeted therapeutics is dependent on the preferential expression of tumor-associated antigens (TAA) at targetable levels on the tumor. Tumor-associated antigens can be generated de novo or can arise from altered expression of normal basal proteins, such as the up-regulation of human epidermal growth factor receptor 2 (Her2/ErbB2). To properly assess the development of Her2 therapeutics in an immune tolerant model, we previously generated a transgenic mouse model in which expression of the human Her2 protein was present in both the brain and mammary tissue. This mouse model has facilitated the development of Her2 targeted therapies in a clinically relevant and suitable model. While heterozygous Her2+/- mice appear to develop in a similar manner to wild type mice (Her2-/-), it has proven difficult to generate homozygous Her2+/+ mice, potentially due to embryonic lethality. In this study, we performed whole genome sequencing to determine if the integration site of the Her2 transgene was responsible for this lethality. Indeed, we report that the Her2 transgene had integrated into the Pds5b (precocious dissociation of sisters) gene on chromosome 5, as a 162 copy concatemer. Furthermore, our findings demonstrate that Her2+/+ mice, similar to Pds5b-/- mice, are embryonic lethal and confirm the necessity for Pds5b in embryonic development. This study confirms the value of whole genome sequencing in determining the integration site of transgenes to gain insight into associated phenotypes.
Cancer Immunology Research Program, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, 3010, Australia.
Carmen S M
CS
Yong
Cancer Immunology Research Program, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, 3010, Australia.
Janelle
J
Sharkey
Cancer Immunology Research Program, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, 3010, Australia.
Belinda
B
Duscio
Cancer Immunology Research Program, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, 3010, Australia.
Ben
B
Venville
Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan, United States of America; Karmanos Cancer Institute, Detroit, Michigan, United States of America.
Wei-Zen
WZ
Wei
Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan, United States of America; Karmanos Cancer Institute, Detroit, Michigan, United States of America.
Richard F
RF
Jones
Cancer Immunology Research Program, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, 3010, Australia.
Clare Y
CY
Slaney
Molecular Genomics Core, Peter MacCallum Cancer Centre, East Melbourne, Victoria, 3002, Australia.
Gisela
G
Mir Arnau
Molecular Genomics Core, Peter MacCallum Cancer Centre, East Melbourne, Victoria, 3002, Australia; Bioinformatics and Cancer Genomics, Peter MacCallum Cancer Centre, East Melbourne, Victoria, 3002, Australia; Bioinformatics Division, The Walter & Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria, 3010, Australia.
Anthony T
AT
Papenfuss
Bioinformatics and Cancer Genomics, Peter MacCallum Cancer Centre, East Melbourne, Victoria, 3002, Australia; Bioinformatics Division, The Walter & Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria, 3010, Australia; Department of Computing and Information Systems, University of Melbourne, Parkville, Victoria, 3010, Australia.
Jan
J
Schröder
Cancer Immunology Research Program, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, 3010, Australia; Department of Immunology, Monash University, Prahran Victoria, 3181, Australia.
Phillip K
PK
Darcy
Cancer Immunology Research Program, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, 3010, Australia; Department of Immunology, Monash University, Prahran Victoria, 3181, Australia.
Michael H
MH
Kershaw
D000818:Animals; D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons; D005313:Fetal Death; D005804:Genes, Lethal; D018734:Genes, erbB-2; D006720:Homozygote; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D014157:Transcription Factors / Q000235:genetics*
D004268:DNA-Binding Proteins; C524054:PDS5B protein, mouse; D014157:Transcription Factors