Thyroid hormone homeostasis and action in the type 2 deiodinase-deficient rodent brain during development.
Considerable indirect evidence suggests that the type 2 deiodinase (D2) generates T3 from T4 for local use in specific tissues such as pituitary, brown fat, and brain, and studies with a D2-deficent mouse, the D2 knockout (D2KO) mouse, have shown this to be the case in pituitary and brown fat. The present study employs the D2KO mouse to determine the role of D2 in the developing brain. As expected, the T3 content in the neonatal D2KO brain was markedly reduced to a level comparable with that seen in the hypothyroid neonatal wild-type mouse. However, the mRNA levels of several T3-responsive genes were either unaffected or much less affected in the brain of the D2KO mouse than in that of the hypothyroid mouse, and compared with the hypothyroid mouse, the D2KO mouse exhibited a very mild neurological phenotype. The current view of thyroid hormone homeostasis in the brain dictates that the T3 present in neurons is generated mostly, if not exclusively, from T4 by the D2 in glial cells. This view is inadequate to explain the findings presented herein, and it is suggested that important compensatory mechanisms must be in play in the brain to minimize functional abnormalities in the absence of the D2.
Galton
Valerie Anne
VA
Department of Physiology, Dartmouth Medical School, 1 Medical Center Drive, Lebanon, New Hampshire 03756, USA. Val.galton@dartmouth.edu
Wood
Emily T
ET
St Germain
Emily A
EA
Withrow
Cheryl-Ann
CA
Aldrich
George
G
St Germain
Genevieve M
GM
Clark
Ann S
AS
St Germain
Donald L
DL
D002001:Adipose Tissue, Brown / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001007:Anxiety / Q000523:psychology; D001921:Brain / Q000254:growth & development / Q000378:metabolism*; D015870:Gene Expression; D006706:Homeostasis / Q000502:physiology*; D007453:Iodide Peroxidase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018782:Maze Learning; D008562:Membrane Glycoproteins / Q000235:genetics; D008568:Memory / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051579:Neurogranin / Q000235:genetics; D009483:Neuropsychological Tests; D010902:Pituitary Gland / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013963:Thyroid Hormones / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D013974:Thyroxine / Q000097:blood / Q000378:metabolism / Q000502:physiology; D013997:Time Factors; D014284:Triiodothyronine / Q000097:blood / Q000378:metabolism / Q000502:physiology; D000097564:Iodothyronine Deiodinase Type II; D020813:Receptor, trkB
D007453:Iodide Peroxidase; D008562:Membrane Glycoproteins; D051579:Neurogranin; D011505:Protein-Tyrosine Kinases; D012333:RNA, Messenger; D013963:Thyroid Hormones; D013974:Thyroxine; D014284:Triiodothyronine; D000097564:Iodothyronine Deiodinase Type II; C496650:Nrgn protein, mouse; C064371:Ntrk2 protein, mouse; D020813:Receptor, trkB