Impaired astrocytic extracellular matrix distribution under congenital hypothyroidism affects neuronal development in vitro

Abstract

Astrocytes clearly play a role in neuronal development. An indirect mechanism of thyroid hormone (T3) in the regulation of neuronal development mediated by astrocytes has been proposed. T3 alters the production and organization of the extracellular matrix (ECM) proteins and proteoglycans, producing a high-quality substrate for neuronal differentiation. The present study investigated the effect of hypothyroidism on the astrocyte production of fibronectin (FN) and laminin (LN) as well as their involvement in neuronal growth and neuritogenesis. Our results demonstrated that the amount of both FN and LN were significantly reduced in cultures of hypothyroid astrocytes from rat cerebellum compared with normal cells. This effect was accompanied by reduced numbers of neurons and neuritogenesis. Similarly, the proportions of neurons and neurons with neurites were reduced in cultures on ECM prepared from hypothyroid astrocytes in comparison with normal cells. The proportion of both normal and hypothyroid neurons is strongly reduced in astrocyte ECM compared with cocultures on astrocyte monolayers, suggesting that extracellular factors other than ECM proteins are involved in this process. Moreover, treatment of hypothyroid astrocytic cultures with T3 restored the area of both FN and LN immunostaining to normal levels and partially reestablished neuronal survival and neuritogenesis. Taken together, our results demonstrated that hypothyroidism involves impairment of the astrocytic microenvironment and affects the production of ECM proteins. Thus, hypothyroidism is implicated in impaired neuronal development.

Thyroid Hormone and Astroglia: Endocrine Control of the Neural Environment

“…We have previously demonstrated that T3 regulates the expression of extracellular matrix proteins through FGF2 and EGF and induces astrocytes to promote neurite outgrowth in vitro . This finding is corroborated by in vivo data showing that hypothyroidism impairs the production and organisation of laminin and fibronectin by astrocytes . We have also shown that the extracellular matrix of hypothyroid astrocytes is less supportive of neuronal growth, whereas T3 treatment of hypothyroid astrocyte cultures restores the production of both fibronectin and laminin to normal levels and rescues the neuronal survival and neuritogenesis deficits of hypothyroid astrocytes .…”

“…Moreover, EGF secreted by cerebellar astrocytes after T3 stimulation regulates extracellular matrix production in these cells in an autocrine manner, through MAPK/PI3K pathways . Consistent with a role for THs in cerebellar astrocyte extracellular matrix production, hypothyroidism reduces the amount of both fibronectin and laminin in cultured cerebellar astrocytes, whereas T3 treatment restores the level of these molecules . Indeed, the distribution areas of both laminin and fibronectin were reduced by more than 50% in hypothyroid astrocyte cultures.…”

Thyroid hormone treated astrocytes induce maturation of cerebral cortical neurons through modulation of proteoglycan levels

“…This is supported by the fact that a direct T3-regulation has not been undoubtedly reported for LN and FN, whereas several growth factors secreted by astrocytes in response to thyroid hormone, like EGF and FGF2, have been shown to modulate ECM components (Calloni et al, 2001; Martinez and Gomes, 2002; Mendes-De-Aguiar et al, 2010). Our data agree with those obtained from Farwell and Dubord-Tomasetti who demonstrated that T4, but not T3, increases LN expression (Farwell and Dubord-Tomasetti, 1999a,b).…”

“…These events result from the synthesis and secretion of soluble factors, such as epidermal growth factor (EGF), and the ECM molecules laminin (LN), fibronectin (FN) and syndecans, producing a substrate for neuronal maturation (Mendes-De-Aguiar et al, 2008, 2010). …”

Comparison of Individual and Combined Effects of Four Endocrine Disruptors on Estrogen Receptor Beta Transcription in Cerebellar Cell Culture: The Modulatory Role of Estradiol and Triiodo-Thyronine

“…For example, in individuals with hypothyroidism the migration and terminal differentiation of granule cell precursors could be impaired [ 8 ]. Developmental abnormalities can also lie on the grounds of altered glia differentiation or due to insufficient TR-ligand interactions [ 10 , 11 , 12 ]. Available data suggest that E2 and THs are equally important regulators of cerebellar development [ 13 , 14 ].…”