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Maternal hypothyroidism and fetal brain development in the rat: Regulation of cytoskeletal protein expression

Sampson, David; (2003) Maternal hypothyroidism and fetal brain development in the rat: Regulation of cytoskeletal protein expression. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Maternal thyroid hormone (TH) is transferred to the conceptus throughout pregnancy and is postulated to regulate fetal brain development. However, maternal TH-dependent stages of brain development remain uncharacterised. A partially thyroidectomised rat dam model was employed to investigate the effect of maternal hypothyroidism on cytoskeletal protein expression in fetal brain. Vimentin protein and nestin mRNA were unaffected, suggesting normal acquisition of neural precursors. Maternal hypothyroidism disturbed protein expression of the neuronal differentiation markers, α-internexin (α-IN) and neurofilament-L from before the onset of fetal TH synthesis until near term, suggestive of delayed neuronal differentiation. Astrocytic differentiation, as judged by Protein and mRNA expression of the astrocytic differentiation marker, glial fibrillary acidic protein, was also deficient, but only near term, as was the expression of α-tubulin and β-tubulin protein isoforms. Maternal TH may regulate fetal brain development by direct action, or indirectly via mechanisms involving the placenta and/or maternal tissues. Therefore, a primary cell culture model was established to investigate the hypothesis that TH directly regulates early neuronal differentiation. This model confirmed that α-IN protein but not mRNA expression was regulated by physiological levels of 3,5,3'-triiodothyronine (T3). Differential display RT-PCR was used to identify primary gene targets of T3 in early differentiating neurons. Around 32 fragments were differentially expressed. Of these, 3 were identified as encoding γ-interferon-inducible protein-10, cyclin ania-6a and the cell division cycle protein-42. However, T3-regulation of these genes could not be confirmed in further cell cultures. In conclusion, maternal hypothyroidism disturbs early neuronal differentiation, possibly via interference with direct action of maternal TH on early fetal brain neurons. Astrocytic development is also deficient during late pregnancy. Deficits in neuronal and glial maturation may underlie the irreversible neurological damage seen in offspring of hypothyroid mothers.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Maternal hypothyroidism and fetal brain development in the rat: Regulation of cytoskeletal protein expression
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Health and environmental sciences; Brain development
URI: https://discovery.ucl.ac.uk/id/eprint/10099462
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