Maternal transmission of an Igf2r domain 11: IGF2 binding mutant allele (Igf2rI1565A) results in partial lethality, overgrowth and intestinal adenoma progression
| Autor: | Francis G. Szele, Susana Frago, Nicholas B. Davies, Mirvat Surakhy, Martin Ducker, Claudia Bühnemann, Matthew P. Crump, Emma J. Carter, Sermet Can, Roman Trikin, A. Bassim Hassan, Jennifer Hughes |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male endocrine system diseases Placenta lcsh:Medicine Receptor IGF Type 2 Mice 0302 clinical medicine Loss of Function Mutation Pregnancy lcsh:Science Receptor Growth Disorders Multidisciplinary Homozygote Imprinting Intrauterine growth medicine.anatomical_structure Disease Progression Female Maternal Inheritance Adenoma Heterozygote Mice Transgenic Biology Article 03 medical and health sciences Genomic Imprinting Protein Domains Insulin-Like Growth Factor II Intestinal Neoplasms medicine Gene silencing Animals Humans Binding site Allele Cancer models Alleles Cell Proliferation Hyperplasia lcsh:R Insulin-like growth factor 2 receptor Heterozygote advantage medicine.disease Embryo Mammalian Molecular biology Disease Models Animal 030104 developmental biology HEK293 Cells lcsh:Q 030217 neurology & neurosurgery |
| Zdroj: | Scientific Reports Hughes, J, Surakhy, M, Can, S, Ducker, M, Davies, N, Szele, F, Bühnemann, C, Carter, E, Trikin, R, Crump, M P, Frago, S & Hassan, A B 2019, ' Maternal transmission of an Igf2r domain 11 : IGF2 binding mutant allele (Igf2r I1565A ) results in partial lethality, overgrowth and intestinal adenoma progression ', Scientific Reports, vol. 9, no. 1, 11388 . https://doi.org/10.1038/s41598-019-47827-9 Scientific Reports, Vol 9, Iss 1, Pp 1-16 (2019) |
| ISSN: | 2045-2322 |
| Popis: | The cation-independent mannose 6-phosphate/insulin-like growth factor-2 receptor (M6P/IGF2R or IGF2R) traffics IGF2 and M6P ligands between pre-lysosomal and extra-cellular compartments. Specific IGF2 and M6P high-affinity binding occurs via domain-11 and domains-3-5-9, respectively. Mammalian maternal Igf2r allele expression exceeds the paternal allele due to imprinting (silencing). Igf2r null-allele maternal transmission results in placenta and heart over-growth and perinatal lethality (>90%) due to raised extra-cellular IGF2 secondary to impaired ligand clearance. It remains unknown if the phenotype is due to either ligand alone, or to both ligands. Here, we evaluate Igf2r specific loss-of-function of the domain-11 IGF2 binding site by replacing isoleucine with alanine in the CD loop (exon 34, I1565A), a mutation also detected in cancers. Igf2rI1565A/+p maternal transmission (heterozygote), resulted in placental and embryonic over-growth with reduced neonatal lethality (80%) observed in homozygotes (Igf2rI1565A/I1565A) suggested that wild-type paternal allele expression attenuates the heterozygote phenotype. To evaluate Igf2r tumour suppressor function, we utilised intestinal adenoma models known to be Igf2 dependent. Bi-allelic Igf2r expression suppressed intestinal adenoma (ApcMin). Igf2rI1565A/+p in a conditional model (Lgr5-Cre, Apcloxp/loxp) resulted in worse survival and increased adenoma proliferation. Growth, survival and intestinal adenoma appear dependent on IGF2R-domain-11 IGF2 binding. |
| Databáze: | OpenAIRE |
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