Delayed development of specific thyroid hormone - regulated events in 1 transthyretin null mice . 2 3

33 Thyroid hormones (THs) are vital for normal postnatal development. Extracellular TH distributor 34 proteins create an intravascular reservoir of THs. Transthyretin (TTR) is a TH distributor protein in the 35 circulatory system and is the only TH distributor protein synthesised in the central nervous system. We 36 investigated the phenotype of TTR null mice during development. Total and free T4 (3’,5’,3,537 tetraiodo-L-thyronine) and free T3 (3’,3,5-triiodo-L-thyronine) in plasma were significantly reduced in 38 14 day old (P14) TTR null mice. TTR null mice also displayed a delayed suckling-to-weaning 39 transition, decreased muscle mass, delayed growth and retarded longitudinal bone growth. In addition, 40 ileums from postnatal day 0 (P0) TTR null mice displayed disordered architecture and contained fewer 41 goblet cells than wild type. Protein concentrations in cerebrospinal fluid from P0 and P14 TTR null 42 mice were higher than in age-matched wild type mice. In contrast to the current literature based on 43 analyses of adult TTR null mice, our results demonstrate that TTR has an important and non44 redundant role in influencing the development of several organs. 45 46