Altered gene dosage confirms the genetic interaction between FIAT and αNAC.
Factor inhibiting ATF4-mediated transcription (FIAT) interacts with Nascent polypeptide associated complex and coregulator alpha (αNAC). In cultured osteoblastic cells, this interaction contributes to maximal FIAT-mediated inhibition of Osteocalcin (Ocn) gene transcription. We set out to demonstrate the physiological relevance of this interaction by altering gene dosage in compound Fiat and Naca (encoding αNAC) heterozygous mice. Compound Naca(+/-); Fiat(+/-) heterozygous animals were viable, developed normally, and exhibited no significant difference in body weight compared with control littermate genotypes. Animals with a single Fiat allele had reduced Fiat mRNA expression without changes in the expression of related family members. Expression of the osteocyte differentiation marker Dmp1 was elevated in compound heterozygotes. Static histomorphometry parameters were assessed at 8weeks of age using microcomputed tomography (μCT). Trabecular measurements were not different between genotypes. Cortical thickness and area were not affected by gene dosage, but we measured a significant increase in cortical porosity in compound heterozygous mice, without changes in biomechanical parameters. The bone phenotype of compound Naca(+/-); Fiat(+/-) heterozygotes confirms that FIAT and αNAC are part of a common genetic pathway and support a role for the FIAT/αNAC interaction in normal bone physiology.
Research Unit, Shriners Hospital for Children - Canada, Montreal, Quebec H3G 1A6, Canada; Department of Human Genetics, McGill University, Montreal, Quebec H3A 2T5, Canada.
Bahareh
B
Hekmatnejad
Research Unit, Shriners Hospital for Children - Canada, Montreal, Quebec H3G 1A6, Canada; Department of Human Genetics, McGill University, Montreal, Quebec H3A 2T5, Canada.
Vice
V
Mandic
Research Unit, Shriners Hospital for Children - Canada, Montreal, Quebec H3G 1A6, Canada; Department of Human Genetics, McGill University, Montreal, Quebec H3A 2T5, Canada.
Vionnie W C
VW
Yu
Research Unit, Shriners Hospital for Children - Canada, Montreal, Quebec H3G 1A6, Canada; Department of Human Genetics, McGill University, Montreal, Quebec H3A 2T5, Canada.
Omar
O
Akhouayri
Research Unit, Shriners Hospital for Children - Canada, Montreal, Quebec H3G 1A6, Canada.
Alice
A
Arabian
Research Unit, Shriners Hospital for Children - Canada, Montreal, Quebec H3G 1A6, Canada; Department of Human Genetics, McGill University, Montreal, Quebec H3A 2T5, Canada; Department of Surgery, McGill University, Montreal, Quebec H3A 2T5, Canada; Department of Medicine, McGill University, Montreal, Quebec H3A 2T5, Canada. Electronic address: rst-arnaud@shriners.mcgill.ca.
René
R
St-Arnaud
D000818:Animals; D001696:Biomechanical Phenomena; D001846:Bone Development / Q000235:genetics; D001842:Bone and Bones / Q000502:physiology; D056970:Co-Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D004843:Epistasis, Genetic; D005260:Female; D018628:Gene Dosage; D015870:Gene Expression; D006579:Heterozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype
D056970:Co-Repressor Proteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; C502605:Txlng protein, mouse; C096099:nascent-polypeptide-associated complex
Bone; Cortical porosity; Factor inhibiting ATF4-mediated transcription (FIAT); Nascent polypeptide associated complex and coregulator alpha (αNAC)