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Gene expression in the developing cerebellum during perinatal hypo- and hyperthyroidism
B C Figueiredo1, G Almazan, Y Ma
1Department of Pharmacology and Therapeutics, McGill University, Montreal, Que., Canada.
Insights
Thyroid hormone imbalance in rats significantly impacts cerebellar development. Hypothyroidism elevates p75NGFR and neurite growth factors, while hyperthyroidism influences myelination, affecting neuronal outgrowth and development.
Area of Science:
- Neuroscience
- Developmental Biology
- Endocrinology
Background:
- Thyroid hormones are crucial for mammalian brain development, particularly cerebellar maturation.
- Imbalances in thyroid hormone levels during the perinatal period can lead to significant neurodevelopmental deficits.
- The p75 neurotrophin receptor (p75NGFR) and myelin proteins (MBP, PLP) are key markers in cerebellar development.
Purpose of the Study:
- To investigate the effects of perinatal thyroid hormone imbalance on gene expression and protein levels in the developing rat cerebellum.
- To elucidate the role of thyroid hormone in regulating genes associated with neuronal growth and myelination.
- To examine the impact of hypothyroidism and hyperthyroidism on p75NGFR, T alpha 1 alpha-tubulin, GAP-43, MBP, and PLP.
Main Methods:
- Quantitative measurement of p75NGFR receptor-like immunoreactivity.
- Analysis of mRNA levels for p75NGFR, T alpha 1 alpha-tubulin, GAP-43, MBP, and PLP in rat cerebellar tissue.
- Comparison between control, hypothyroid, and hyperthyroid rat models at various postnatal days (P15, P30).
Main Results:
- Hypothyroidism led to a striking elevation in p75NGFR immunoreactivity and increased mRNA for T alpha 1 alpha-tubulin and GAP-43.
- Neuronal abnormalities, including axonal varicosities, were observed in Purkinje cells of hypothyroid rats.
- Thyroid hormone imbalance differentially affected myelin protein gene expression; hyperthyroidism increased MBP and PLP mRNA levels early on, while hypothyroidism caused a decrease later.
Conclusions:
- Thyroid hormone plays a critical role in the early stages of cerebellar myelination.
- Hypothyroidism induces specific changes in gene expression related to neuronal outgrowth and p75NGFR signaling.
- These findings provide in vivo evidence for differential gene regulation by thyroid hormone in the developing cerebellum, impacting neuronal development and myelination.
Abstract:
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.