Endocrine Abstracts (2009) 19 OC1

Alternative splicing of the thyroid hormone receptor [alpha] gene regulates skeletal development

TM Galliford, A Ghaffar, JHD Bassett & GR Williams


Molecular Endocrinology Group, MRC CSC, Hammersmith Campus, Imperial College, London, UK.


T3 regulates bone development and its actions are mediated by TRα and TRβ. Using TR knockout mice we demonstrated that TRα1 is the predominant mediator of T3 action in bone, although TRα2 (a non-T3 binding isoform of unknown function) and TRβ1 are also expressed in the skeleton. We show that mice lacking TRα2 have characteristic skeletal abnormalities of delayed closure of the skull sutures, abnormal clavicle development and reduced bone mineralization; a phenotype that recapitulates human cleidocranial dysplasia. By contrast, mice lacking TRα1 have delayed cartilage development and growth retardation. Thus, we hypothesized TRα mRNA splicing regulates skeletal development. To investigate, we determined levels of TRα1, TRα2 and TRβ1 expression by qRT-PCR in endochondral (tibia) and intramembranous (skull) bone from neonatal and 4 week-old wild-type mice. In accordance with phenotypes in TR knockout mice, TRα1 mRNA was expressed at 35–40 fold higher levels than TRβ1 in neonatal skull and tibia. At 4 weeks, however, levels of TRα1 and TRβ1 were equivalent in skull, but TRα1 expression remained 6 fold higher in tibia. By contrast, TRα1 mRNA expression was 2.5 fold higher than TRα2 in neonatal intramembranous and endochondral bone, whereas the ratio of TRα1:TRα2 expression increased to greater than 10 fold at 4 weeks. Previous studies have shown TRα2 is conserved in mammals, present in all tissues examined and always the predominant transcript expressed from the Thra gene. Here we show that bone is the exception because TRα1 expression predominates. Furthermore, although skeletal TRα2 mRNA expression is low, it is maximal in wild-type mice at the time when skeletal abnormalities develop in TRα2 knockout mice. For the first time these studies suggest a functional role for TRα2 in vivo and they indicate that alternative splicing of the Thra gene regulates skeletal development.

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