Hypothyroidism reduces the rate of slow component A (SCa) axonal transport and the amount of transported tubulin in the hyt/hyt mouse optic nerve.
Thyroid hormone deficiency in the developing brain leads to disorders of neuronal process growth. This is evidenced by reduced axonal and dendritic size and complexity (Garza et al.: Developmental Brain Research 43:287-297, 1988; Ruiz-Marcos: Iodine and the Brain. New York: Plenum Press, pp 91-102, 1989). These findings may be related to alterations in the neuronal cytoskeleton in hypothyroidism, such as reduced or abnormal microtubular number and density (Faivre et al.: Developmental Brain Research 8: 21-30, 1983), and altered assembly, stabilization, and composition of microtubule protein in the hypothyroid brain. Neurofilaments also contribute to axonal caliber and process stability. Similar to microtubules, certain properties of neurofilaments are altered in developing hypothyroid axons (Marc and Rabie: International Journal of Developmental Neuroscience 3: 353-358, 1985; Faivre et al.: Developmental Brain Research 8:21-30, 1983) that may affect axonal caliber and process stability. Normal process growth is predicted on formation of appropriate numbers of microtubules and on the normal synthesis and axonal transport of cytoskeletal components [tubulin, microtubule associated proteins (MAPs), and neurofilament proteins]. Hypothyroidism might alter the neuronal cytoskeleton and neuronal growth either by affecting the developmental programs for expression of specific isoforms of cytoskeletal proteins or by changing the delivery of cytoskeletal proteins via slow axonal transport, particularly slow component a (SCa). Previous studies had demonstrated changes in the amount of specific microtubule protein isoforms and mRNAs (Stein et al.: Iodine and the Brain. New York: Plenum Press, pp 59-78, 1989a). To further elucidate the molecular basis for process growth abnormalities in the hypothyroid brain, we investigated slow axonal transport in the mouse to determine the effects of thyroid hormone deficiency on the rate and composition of SCa. Comparisons of SCa in the optic nerve of hyt/hyt hypothyroid mouse and euthyroid hyt/+ littermates and euthyroid progenitor strain, BALB/cBY +/+ mice, indicated that the velocity of SCa was significantly reduced in hyt/hyt optic nerve relative to hyt/+ and +/+. The axonal transport rate for tubulin, which is carried in SCa, was 0.118 mm/day in the hyt/hyt optic nerves. This rate was significantly different for the tubulin rates for the hyt/+ optic nerves (0.127 mm/day) and for the +/+ optic nerves (0.138 mm/day). Neurofilament proteins, as measured by the 140,000 daltons component, NFM, also appeared to be reduced in velocity in the hyt/hyt versus the hyt/+ and +/+ optic nerves.(ABSTRACT TRUNCATED AT 400 WORDS)
Stein
S A
SA
Department of Neurology, University of Texas Southwestern Medical Center, Dallas 75235.
Kirkpatrick
L L
LL
Shanklin
D R
DR
Adams
P M
PM
Brady
S T
ST
D000199:Actins / Q000032:analysis; D000818:Animals; D001370:Axonal Transport / Q000502:physiology*; D003599:Cytoskeleton / Q000502:physiology* / Q000648:ultrastructure; D007037:Hypothyroidism / Q000235:genetics / Q000503:physiopathology*; D007381:Intermediate Filament Proteins / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains / Q000502:physiology*; D008959:Models, Neurological; D016900:Neurofilament Proteins; D009900:Optic Nerve / Q000503:physiopathology*; D013974:Thyroxine / Q000097:blood; D014404:Tubulin / Q000378:metabolism*
D000199:Actins; D007381:Intermediate Filament Proteins; D016900:Neurofilament Proteins; D014404:Tubulin; D013974:Thyroxine