Molecular Basis of Thyroid Hormone-Dependent Brain Development*

Oppenheimer, Jack H.; Schwartz, Harold L.

doi:10.1210/edrv.18.4.0309

Cited by 209 publications

(123 citation statements)

References 134 publications

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“…Behavioral consequences of developmental or adult thyroid dysfunction are mediated by actions of thyroid hormones on thyroid hormone receptors (TR), predominantly by positive or negative transcriptional regulation of thyroid hormone responsive genes [39]. The ligandactivated nuclear TR isoforms, TRα1, TRβ1 and TRβ2, are produced by alternative splicing of the primary transcripts of the TRα and TRβ genes, respectively [52,58].…”

Section: Introductionmentioning

confidence: 99%

Behavioral inhibition and impaired spatial learning and memory in hypothyroid mice lacking thyroid hormone receptor α

Wilcoxon

Nadolski

Samarut

et al. 2007

Behavioural Brain Research

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Thyroid hormone insufficiency leads to impaired neurogenesis, behavioral alterations and cognitive deficits. Thyroid hormone receptors, expressed in brain regions involved in these behaviors, mediate the effects of thyroid hormone deficiency or excess. To determine the contribution of thyroid hormone receptor alpha (TRα) in these behaviors, we examined the behavior of euthyroid as well as hypo-and hyperthyroid mice lacking all isoforms of the TRα (TRα o/o ). The hypothyroxinemic TRα o/o mice demonstrated behavioral inhibition, manifested in decreased activity and increased anxiety/fear in the open field test (OFT) and increased immobility in the forced swim test (FST) compared to C57BL/6J mice. TRα o/o mice also showed learning and recall impairments in the Morris water maze (MWM), which were exaggerated by hypothyroidism in TRα o/o mice. These impairments were concurrent with increased thigmotaxis, suggesting an increased anxiety-like state of the TRα o/o mice in the MWM. Expression of genes, known to be involved in processes modulating learning and memory, such as glucocorticoid receptor (GR), growth-associated protein 43 (GAP-43) and neurogranin (RC3), were significantly decreased in the hippocampus of TRα o/o mice. GR expression was also decreased in the frontal cortex and amygdala of TRα o/o mice, indicating that expression of GR is regulated, probably developmentally, by one or more isoforms of TRα in the mouse brain. Taken together these data demonstrate behavioral alterations in the TRα o/o mice, indicating the functional role of TRα, and a delicate interaction between TRα and TRβ-regulated genes in these behaviors. Thyroid hormone-regulated genes potentially responsible for the learning deficit found in TRα o/o mice include GR, RC3 and GAP-43.

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Section: Introductionmentioning

confidence: 99%

Behavioral inhibition and impaired spatial learning and memory in hypothyroid mice lacking thyroid hormone receptor α

Wilcoxon

Nadolski

Samarut

et al. 2007

Behavioural Brain Research

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“…During the late embryonic postnatal period, T3 action is critical for brain development. However, although both hyperthyroidism and hypothyroidism are known to affect directly or indirectly the proliferation, apoptosis, migration, and differentiation of several neuronal and glial cell types (1,2), only subtle brain defects have been reported to date in the nervous system of TR knockout mice (3,4). Moreover, knock-in point mutations recently led to contrasting results that are difficult to interpret (5)(6)(7).…”

mentioning

confidence: 99%

Persistence of oligodendrocyte precursor cells and altered myelination in optic nerve associated to retina degeneration in mice devoid of all thyroid hormone receptors

Baas

Legrand

Samarut

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Thyroid hormone (3,5,3-triiodo-L-thyronine or T3) exerts a pleiotropic activity during central nervous system development. Hypothyroidism during the fetal and postnatal life results in an irreversible mental retardation syndrome. At the cellular level, T3 is known to act on neuronal and glial lineages and to control cell proliferation, apoptosis, migration, and differentiation. Oligodendrocyte precursor cells (OPC) found at birth in the optic nerves are self-renewing cells that normally differentiate during the first 3 weeks of rodent postnatal life into postmitotic myelinating oligodendrocytes. In vitro, the addition of T3 to OPC is sufficient to trigger their terminal differentiation. The present analysis of T3 receptor knockout mice reveals that the absence of all T3 receptor results in the persistence of OPC proliferation in adult optic nerves, in a default in myelination, and sometimes in the degeneration of the retinal ganglion neurons. Thus, T3 signaling is necessary in vivo to promote the complete differentiation of OPC. T hyroid hormone (3,5,3Ј-triiodo-L-thyronine, T3) acts directly at the transcription level by binding to nuclear receptors (TR␣1 and TR␤1, TR␤2, TR␤3) encoded by both TR␣ and TR␤ genes to control a number of physiological and developmental processes. During the late embryonic postnatal period, T3 action is critical for brain development. However, although both hyperthyroidism and hypothyroidism are known to affect directly or indirectly the proliferation, apoptosis, migration, and differentiation of several neuronal and glial cell types (1, 2), only subtle brain defects have been reported to date in the nervous system of TR knockout mice (3, 4). Moreover, knock-in point mutations recently led to contrasting results that are difficult to interpret (5-7). In the rodent optic nerves, oligodendrocyte precursor cells (OPC) differentiate during the first postnatal weeks to give rise to the oligodendrocytes that synthesize myelin around the axons of the retinal ganglion cells (RGC). The in vitro culture of newborn optic nerve OPC (8-10) has offered a unique opportunity to study the precise influence of T3 on the differentiation of this category of glial cells (reviewed in ref. 10). This in vitro model has been extensively investigated, and a number of studies confirmed the direct effect of T3 on OPC differentiation. However, the fact that retinoic acid or glucocorticoids can substitute to T3 to trigger in vitro OPC differentiation (9, 11) raises the question of the respective importance of these factors in vivo. The respective contribution of TR␣ and TR␤ in OPC hormonal response is also unclear (8,10,12). TR␣ is expressed at all stages of oligodendrocyte differentiation, whereas the status for TR␤ remains controversial. Based on RNA and protein analysis, TR␤ expression has been reported to be restricted to differentiated oligodendrocytes (13-16) or to occur in both OPC and oligodendrocytes (9, 17). To clarify the importance of T3 action in vivo and the respective functions of TR␣ and TR␤ in OPC...

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“…Similarly, mice carrying the Myo5a d-n2J mutation that eliminates the last 92 residues of the myosin V tail also show severe neurological defects during postnatal life. These defects in cerebellar development are reminiscent of the cerebellar defects and developmental delays in brain maturation that are often associated with neonatal hypothyroidism (41,42), and the mapping of the neurological defects in dilute strains to the hormone-dependent vesicle-binding domain of myosin 5a provides an important clue to one of the molecular events that mediates the morphogenic effects of T 4 in brain.…”

Section: Discussionmentioning

confidence: 99%

Real-time Visualization of Processive Myosin 5a-mediated Vesicle Movement in Living Astrocytes

Stachelek

Tuft

Lifschitz

et al. 2001

Journal of Biological Chemistry

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Recycling endosomes in astrocytes show hormoneregulated, actin fiber-dependent delivery to the endosomal sorting pool. Recycling vesicle trafficking was followed in real time using a fusion protein composed of green florescent protein coupled to the 29-kDa subunit of the short-lived, membrane-bound enzyme type 2 deiodinase. Primary endosomes budded from the plasma membrane and oscillated near the cell periphery for 1-4 min. The addition of thyroid hormone triggered the processive, centripetal movement of the recycling vesicle in linear bursts at velocities of up to 200 nm/s. Vesicle migration was hormone-specific and blocked by inhibitors of actin polymerization and myosin ATPase. Domain mapping confirmed that the hormone-dependent vesicle-binding domain was located at the C terminus of the motor. In addition, the interruption of normal dimerization of native myosin 5a monomers inactivated vesicle transport, indicating that single-headed myosin 5a motors do not transport cargo in situ. This is the first demonstration of processive hormone-dependent myosin 5a movement in living cells.The trafficking of intracellular organelles utilizes both microtubules composed of polymerized tubulin and microfilaments composed of polymerized actin (1). Dyneins and kinesins provide bidirectional movement of organelles along individual microtubules, and members of the myosin superfamily use microfilaments for this function. Recent work done in melanocytes revealed that individual organelles can possess both microtubule-and microfilament-based motors and that the two cargo carrier systems cooperate in organelle trafficking (2, 3). Microtubule-based vesicle carriers are responsible for long range vesicle movement in these cells, whereas myosin 5a-mediated vesicle movement is restricted to short-range shuttling along the cortical actin cytoskeleton in the dendritic processes (4).Four of the 18 identified classes of myosin motor proteins appear to transport vesicles along microfilaments in vitro (5), and loss of the two-headed myosin 5a motor disrupts vesicle trafficking in rodents and yeast (1, 2, 6 -13). In melanocytes from the myosin 5a null mouse, dilute, pigment granules remain centrally distributed and fail to accumulate in dendritic arbors (4, 14). The short distances traveled by cargo-laden myosin 5a in melanocytes limit the direct analysis of myosin 5a-mediated movement in living cells. In vitro, myosin 5a is a processive cargo-carrying motor and undergoes multiple catalytic cycles that allow the motor to move long distances along actin fiber tracks by taking large steps of ϳ36 nm (15-17). These estimates of the stepping size of myosin 5a closely agree with the distance between the two motor heads (18). The globular tail of the motor appears to bind tightly to the surface of melanosomes (4), synaptic vesicles (19,20), and recycling vesicles in astrocytes (21). The tail of myosin 5a also shows hormone-regulated vesicle binding (21) and Ca 2ϩ -modulated interactions with two synaptic vesicle proteins, synaptophysin and synapto...

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Molecular Basis of Thyroid Hormone-Dependent Brain Development*

Cited by 209 publications

References 134 publications

Behavioral inhibition and impaired spatial learning and memory in hypothyroid mice lacking thyroid hormone receptor α

Behavioral inhibition and impaired spatial learning and memory in hypothyroid mice lacking thyroid hormone receptor α

Persistence of oligodendrocyte precursor cells and altered myelination in optic nerve associated to retina degeneration in mice devoid of all thyroid hormone receptors

Real-time Visualization of Processive Myosin 5a-mediated Vesicle Movement in Living Astrocytes

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