Hearing loss and retarded cochlear development in mice lacking type 2 iodothyronine deiodinase.
The later stages of cochlear differentiation and the developmental onset of hearing require thyroid hormone. Although thyroid hormone receptors (TRs) are a prerequisite for this process, it is likely that other factors modify TR activity during cochlear development. The mouse cochlea expresses type 2 deiodinase (D2), an enzyme that converts thyroxine, the main form of thyroid hormone in the circulation, into 3,5,3'-triiodothyronine (T3) the major ligand for TRs. Here, we show that D2-deficient mice have circulating thyroid hormone levels that would normally be adequate to allow hearing to develop but they exhibit an auditory phenotype similar to that caused by systemic hypothyroidism or TR deletions. D2-deficient mice have defective auditory function, retarded differentiation of the cochlear inner sulcus and sensory epithelium, and deformity of the tectorial membrane. The similarity of this phenotype to that caused by TR deletions suggests that D2 controls the T3 signal that activates TRs in the cochlea. Thus, D2 is essential for hearing, and the results suggest that this hormone-activating enzyme confers on the cochlea the ability to stimulate its own T3 response at a critical developmental period.
Department of Human Genetics and Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
Lily
L
Ng
Richard J
RJ
Goodyear
Chad A
CA
Woods
Mark J
MJ
Schneider
Edward
E
Diamond
Guy P
GP
Richardson
Matthew W
MW
Kelley
Donald L St
DL
Germain
Valerie Anne
VA
Galton
Douglas
D
Forrest
D000818:Animals; D001483:Base Sequence; D003051:Cochlea / Q000002:abnormalities* / Q000187:drug effects / Q000503:physiopathology; D018076:DNA, Complementary / Q000235:genetics; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D034381:Hearing Loss / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D007453:Iodide Peroxidase / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D013974:Thyroxine / Q000097:blood; D014284:Triiodothyronine / Q000097:blood / Q000494:pharmacology; D000097564:Iodothyronine Deiodinase Type II
D018076:DNA, Complementary; D007453:Iodide Peroxidase; D011988:Receptors, Thyroid Hormone; D013974:Thyroxine; D014284:Triiodothyronine; D000097564:Iodothyronine Deiodinase Type II