Bradley D J, Towle H C, Young W S
Laboratory of Cell Biology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892.
Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):439-43. doi: 10.1073/pnas.91.2.439.
Clinicians have long recognized that congenital deficiency of iodine (a component of thyroid hormone) somehow damages the human embryonic nervous system, causing sensori-neural deafness. Recently, a deletion encompassing most of the human beta thyroid hormone receptor (TR beta) gene has been found in children who are neurologically normal except for one striking defect: profound sensori-neural deafness. We now show that the TR beta gene is prominently expressed very early in rat inner ear development. This expression is remarkable because both TR beta 1 and TR beta 2 mRNAs are restricted, as early as embryonic day 12.5, to that portion of the embryonic inner ear that gives rise to the cochlea, the structure responsible for converting sound into neural impulses. The timing of this expression, when correlated with human inner ear development, raises the possibility that TRs may act in human ontogenesis earlier than previously suspected. These results provide a rare correlation between a specific human neurologic deficit (deafness) and transcription factor expression in a highly discrete embryonic cell population (ventral otocyst). TR alpha gene expression is also prominent in the developing cochlea, but, in contrast to the restricted pattern of TR beta gene expression, TR alpha 1 and TR alpha 2 transcripts are also found in inner ear structures responsible for balance. Deafness in children homozygous for a large deletion in the TR beta gene suggests that cochlear alpha 1 TRs cannot functionally compensate for the absence of TR beta 1 and TR beta 2. The developing inner ear may, therefore, represent an example of TR isoform-specific transcriptional regulation in vivo.
临床医生早就认识到，碘（甲状腺激素的一种成分）先天性缺乏会以某种方式损害人类胚胎神经系统，导致感音神经性耳聋。最近，在一些除了一个明显缺陷——严重感音神经性耳聋外神经系统正常的儿童中，发现了一个涵盖大部分人类β甲状腺激素受体（TRβ）基因的缺失。我们现在表明，TRβ基因在大鼠内耳发育的早期就显著表达。这种表达很显著，因为早在胚胎第12.5天，TRβ1和TRβ2 mRNA就局限于胚胎内耳中产生耳蜗的部分，耳蜗是负责将声音转化为神经冲动的结构。这种表达的时间与人类内耳发育相关，这增加了TRs可能在人类个体发育中比之前怀疑的更早发挥作用的可能性。这些结果在特定的人类神经缺陷（耳聋）与高度离散的胚胎细胞群体（腹侧耳囊）中的转录因子表达之间提供了罕见的关联。TRα基因在发育中的耳蜗中也有显著表达，但与TRβ基因表达的局限模式不同，TRα1和TRα2转录本也在内耳负责平衡的结构中被发现。TRβ基因大片段缺失的纯合子儿童出现耳聋表明，耳蜗α1 TRs在功能上无法补偿TRβ1和TRβ2的缺失。因此，发育中的内耳可能代表了体内TR亚型特异性转录调控的一个例子。
