Figueiredo B C, Almazan G, Ma Y, Tetzlaff W, Miller F D, Cuello A C
Department of Pharmacology and Therapeutics, McGill University, Montreal, Que., Canada.
Brain Res Mol Brain Res. 1993 Mar;17(3-4):258-68. doi: 10.1016/0169-328x(93)90010-m.
The intensity of p75NGFR receptor-like immunoreactivity and the mRNAs encoding p75NGFR, T alpha 1 alpha-tubulin, GAP-43 and the myelin proteins MBP and PLP were measured in the developing cerebellum to study the effects of perinatal thyroid hormone imbalance in rats. Results compared to age-matched controls provide in vivo evidence for differential gene regulation by thyroid hormone in the developing cerebellum. We found that p75NGFR immunoreactivity was strikingly elevated in hypothyroid rats, whereas p75NGFR mRNA content remained only twice as high as that of control levels on postnatal day 15 (P15). When p75NGFR immunoreactivity was still elevated in hypothyroid rats, Purkinje cells exhibited proximal axonal varicosities, axonal twisting and differences in axonal caliber. The mRNAs encoding proteins involved with neurite growth-promoting elements, T alpha 1 alpha-tubulin and GAP-43, were also increased in hypothyroidism, possibly reflecting a neuronal response to a deficiency in, or damage to, cerebellar neurons, or a general delay in their down regulation. Similar increases were not observed for the myelin specific genes. MBP and PLP mRNAs were first detected on P2 of hyperthyroid rats, and they increased with age. Hypo- or hyperthyroidism did not affect the initial onset of MBP and PLP expression, however, hyperthyroidism increased levels of PLP and MBP mRNAs between P2 and P10. By contrast, the most consistent decrease in MBP and PLP mRNAs in rats with thyroid hormone deficiency was observed only on P10. At later times (P15 and P30), the two mRNA levels were similar to controls in all groups. These results are consistent with a role for thyroid hormone in the earlier stages of cerebellar myelination. Hypothryoidism led to specific increases in T alpha 1 alpha-tubulin and GAP-43 mRNAs, and in the immunoreactivity and mRNA levels of p75NGFR receptor--all changes that may play a role in the observed abnormal neuronal outgrowth.
为研究围产期甲状腺激素失衡对大鼠的影响，我们检测了发育中小脑内p75神经营养因子受体（p75NGFR）样免疫反应强度以及编码p75NGFR、α1α-微管蛋白（Tα1α-tubulin）、生长相关蛋白43（GAP-43）和髓鞘蛋白髓鞘碱性蛋白（MBP）及蛋白脂蛋白（PLP）的mRNA水平。与年龄匹配的对照组相比，结果为发育中小脑内甲状腺激素对基因的差异调节提供了体内证据。我们发现，甲状腺功能减退大鼠的p75NGFR免疫反应显著增强，而在出生后第15天（P15），p75NGFR mRNA含量仅为对照水平的两倍。当甲状腺功能减退大鼠的p75NGFR免疫反应仍增强时，浦肯野细胞出现近端轴突膨体、轴突扭曲及轴突直径差异。甲状腺功能减退时，编码与神经突生长促进因子相关蛋白的Tα1α-tubulin和GAP-43的mRNA也增加，这可能反映了神经元对小脑神经元缺乏或损伤的反应，或其下调的普遍延迟。髓鞘特异性基因未观察到类似增加。甲状腺功能亢进大鼠在P2首次检测到MBP和PLP mRNA，且随年龄增加。甲状腺功能减退或亢进均未影响MBP和PLP表达的初始发生，然而，甲状腺功能亢进在P2至P10期间增加了PLP和MBP mRNA水平。相比之下，仅在P10观察到甲状腺激素缺乏大鼠的MBP和PLP mRNA最一致的降低。在后期（P15和P30），所有组中这两种mRNA水平均与对照组相似。这些结果与甲状腺激素在小脑髓鞘形成早期阶段的作用一致。甲状腺功能减退导致Tα1α-tubulin和GAP-43 mRNA特异性增加，以及p75NGFR受体的免疫反应性和mRNA水平增加——所有这些变化可能在观察到的异常神经元生长中起作用。
