Neuroscience Letters 421 (2007) 234–238 Cell division and apoptosis in the adult neural stem cell niche are differentially affected in transthyretin null mice Samantha J. Richardson ∗ , Gregory F. Lemkine, Gladys Alfama, Zahra Hassani, Barbara A. Demeneix UMR CNRS 5166, Evolution des R´ egulations Endocriniennes, Mus´ eum National d’Histoire Naturelle, 7 rue Cuvier, 75231 Paris, France Received 27 February 2007; received in revised form 5 April 2007; accepted 15 May 2007 Abstract Thyroid hormones (THs) are fundamental in regulation of growth and development, particularly of the brain. THs are required for full proliferative activity of neural stem cells in the subventricular zone (SVZ) of adult mouse brains, and also affect the normal fate of progenitor cells: apoptosis. Transthyretin (TTR) is a TH distributor protein in the blood and cerebrospinal fluid. TTR secretion by the choroid plexus is involved in transport of THs from blood into cerebrospinal fluid. We investigated the regulation of neural stem cell cycle in the SVZ of adult TTR null mice. Markers for neural stem cell mitosis that are reduced during hypothyroidism, did not differ between genotypes. However, in TTR null mice the level of apoptosis, the fate of most progenitor cells, was as low as that in brains of hypothyroid wildtype mice. Thus, lack of TTR results in reduced availability of TH to progenitor cells in the SVZ. We show that proliferation and apoptosis in the SVZ neural stem cell niche are differentially affected by the lack of TTR synthesis. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Transthyretin; Brain; Thyroid hormones; Neural stem cells; Hypothyroidism Thyroid hormones (THs) are involved in regulation of growth and development, in particular of the brain. Insufficient TH dur- ing development leads to irreversible brain damage resulting in mental retardation [8]. THs are synthesized in the thyroid gland and secreted into the bloodstream, where they bind TH distributor proteins (THDPs). THs are lipophilic and partition between the lipid and aque- ous phases at 20,000:1. To ensure adequate distribution of THs around the body via the blood, >99% is bound to THDPs, leav- ing <1% available for uptake into tissues. The dissociation rates of THs from THDPs, together with the capillary transit times, determine the availability of free THs to individual tissues. Of the three THDPs in human blood (albumin, TTR and thyroxine- binding globulin), TTR is responsible for most TH delivery to tissues in the body and brain (see [14]). Recently, membrane- bound TH transporters have been identified [19], which assist in uptake of THs into specific tissues. THs include 3 ′ ,5 ′ ,3,5-tetraiodo-l-thyronine (T4), which has higher affinity for THDPs and is the predominant form in blood, ∗ Corresponding author. Tel.: +61 3 9925 7897; fax: +61 3 9925 7063. E-mail address: samantha.richardson@rmit.edu.au (S.J. Richardson). and 5 ′ ,3,5,-triiodo-l-thyronine (T3) which has higher affinity for TH receptors (TRs) [17]. Activation of T4 to T3 and deactiva- tion of T4 and T3 are executed by deiodinases D1, D2 and D3. In the liver, activation of T4 to T3 is carried out mainly by D1, whereas in the brain this is performed by D2. D3 is primarily involved with inactivation of THs (see [5]). Cytosolic TH bind- ing proteins are involved in intracellular trafficking of TH [22]. Within the nucleus T3 binds TRs which dimerize with RXRs (9 cis retinoic acid receptors) and together with co-modulators the complex assembles on TH response elements in the upstream regulatory region of TH responsive genes, thereby regulating gene expression [10]. To regulate transcription of TH responsive genes in the CNS, THs must enter the brain. The choroid plexus forms the blood- cerebrospinal fluid barrier, located in the ventricles of the brain, and produces most of the cerebrospinal fluid (CSF). TTR is the protein most abundantly synthesised and secreted by the choroid plexus of reptiles, birds and mammals (see [14]). TTR synthesised by the choroid plexus is secreted into the CSF and transports T4 from blood into the CSF [14]. The adult mam- malian choroid plexus does not contain deiodinases [18]. T4 entering the CSF via the choroid plexus is deiodinated to T3 via deiodinases in specific subregions of the brain [21]. 0304-3940/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2007.05.040