Deletion of the RNaseIII Enzyme Dicer in Thyroid Follicular Cells Causes Hypothyroidism with Signs of Neoplastic Alterations

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Congenital hypothyroidism (CH) is one of the most common neonatal metabolic disorder (1∶4000) [1]–[3], characterized by a deficiency in the production of thyroid hormones. If untreated early in life, CH can lead to mental retardation and abnormal growth. CH has been associated with loss of function mutations in thyroid specific genes such as Sodium Iodide Symporter (NIS) [4] , Thyroglobulin (TG) [5] , Thyroperoxidase (TPO) [6], H2O2 generating system, DUOX2 [7], and DUOXA2 [8], Pendrin (PDS) [9] or DEHAL1 [10], that result in a reduction of the thyroid hormone production. But the majority of CH cases are due to defects in thyroid organogenesis (ca 85%), with a gland absent (agenesis), abnormally located (ectopy) or severely reduced in size [hypoplasia, as observed for mutations in the Thyrotropin receptor gene (TSHR) [11] [12], [13]. Unfortunately, the underlying molecular mechanisms are poorly understood.

In most species, thyroid organogenesis can be oversimplified into two phases comprising (a) thyroid precursor cells specification, budding and migration of the thyroid primordium, and (b) functional differentiation of thyroid follicular cells [14]. During mouse embryogenesis, thyroid precursor cells can be identified as a subpopulation of cells at the ventral endoderm of the pharyngeal floor by concurrent expression of four transcription factors (TITF1, PAX8, FOXE1, HHEX) [2]. Genetic invalidation of these transcription factors in mouse showed that they are not required for thyroid specification but that loss of any of them results in thyroid dysgenesis. However, mutations found in TITF1, PAX8 (See [15] for review), and FOXE1 [16], together with mutations found in TSHR [11] [17] can only explain a low percentage of CH cases with thyroid development abnormalities [2] [18]. This suggests that thyroid developmental transitions are orchestrated by a network of appropriate molecular events which remain elusive [19] [20] [21].

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In mammals, growing evidence demonstrates that small non-coding RNAs, and in particular microRNAs (miRNAS), play a substantial role in development [22] [23], cell maintenance and disease [24]–[27]. miRNAs are 22-nucleotides long non-coding RNAs, that regulate gene expression in a variety of tissues more commonly by binding to the 3′UTR of target mRNAs, thereby triggering mRNAs degradation or translational repression [reviewed in [28]. Functional maturation of miRNAs requires processing of the primary transcript by Dicer, an RNaseIII-type enzyme [29]. Thus, in the absence of Dicer, miRNA maturation of most miRNAs is blocked [23]. In turn, inactivation of Dicer provides an efficient approach to examine the function of small RNAs, including miRNA and small interfering RNAs (siRNAs), in specific biological processes. To date, the importance of small RNAs for normal organogenesis (e.g., pancreas, brain, lung, heart, ovary) has been demonstrated in several mouse models of tissue-specific Dicer inactivation [30]–[38]. In the present study, we took a global approach to study the role of small RNAs in thyroid organogenesis by invalidating Dicer in thyroid follicular cells.

We have examined the effect of conditional Dicer knockout (cKO) in Pax8-Cre and Tg-Cre transgenic mice, which enabled deletion of floxed Dicer alleles in thyroid follicular cells at E8.5 and E14.5 respectively [2], [39]. In both models, mutant mice die soon after weaning, due to severe hypothyroidism. Dicer inactivation caused thyroid hypoplasia in addition to tissue disorganization and a marked down-regulation of Nis expression. When lethality was delayed in T4 substituted animals, an ongoing de-differentiation of thyroid tissue was observed. Our data show that loss of small RNA maturation due to Dicer inactivation in the thyroid severely disturbs late stages of thyroid organogenesis and progressively results in a cancer-like phenotype. Taken together, our results suggest that small RNAs, likely miRNAs, play an essential role in thyroid homeostasis and raise the possibility that small RNAs may be involved in some human thyroid neoplastic alterations.

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About the Author: Tung Chi