ALPHA-THYROID AND BETA-THYROID HORMONE-RECEPTOR (TR) GENE-EXPRESSION DURING AUDITORY NEUROGENESIS - EVIDENCE FOR TR ISOFORM-SPECIFIC TRANSCRIPTIONAL REGULATION IN-VIVO

Clinicians have long recognized that congenital deficiency of iodine ( a component of thyroid hormone) somehow damages the human embryonic ne rvous system, causing sensori-neural deafness. Recently, a deletion en compassing most of the human beta thyroid hormone receptor (TR beta) g ene has been found in children who are neurologically normal except fo r one striking defect: profound sensori-neural deafness. We now show t hat 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 cochle a, 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 ontogene sis earlier than previously suspected. These results provide a rare co rrelation between a specific human neurologic deficit (deafness) and t ranscription factor expression in a highly discrete embryonic cell pop ulation (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 i n children homozygous for a large deletion in the TR beta gene suggest s that cochlear alpha 1 TRs cannot functionally compensate for the abs ence of TR beta 1 and TR beta 2. The developing inner ear may, therefo re, represent an example of TR isoform specific transcriptional regula tion in vivo.