Thyroid hormone is crucial to CNS development and function. A deficiency of thyroid hormone causes cretinism, a syndrome of severe impairment of physical and mental development. Relatively few genes in brain are known to be induced by thyroid hormone recently, we showed that one of these - Rhes (RasHomologous Enriched in Striatum, also called Dexras 2) - potently stimulates the brain iron transporter, or DMT1. The brain's iron requirement is relatively high. Intense brain metabolism and concomitant oxygen consumption depends upon a steady supply of iron to maintain cytochromes and mitochondrial function. Iron deficiency during pregnancy or postnatal life can result in brain maldevelopment. Administration of supplemental iron to children may not fully compensate for deprivation early in life: cognitive deficits are frequent in these youngsters. Conversely, iron excess can be neurotoxic, in part by favoring formation of reactive oxygen species (ROS). These observations indicate that iron transport into the CNS is a tightly ordered process that satisfies the need of the brain for this element without the imposition of a toxic burden. Our long-term goal is to elucidate the molecular basis and functional importance of iron brain trafficking. In this study, we will use molecular, cellular and biochemical approaches to characterize the function and regulation of Rhes. Our focus is to understand how this agents regulates iron transport and how this process affects neurotransmitter synthesis, which requires iron. Our research will provide insight into the mechanism(s) by which iron or thyroid deficiency hampers brain development. It also may lead to new strategies for the prevention of learning disabilities and for the management of children so affected.
Iron is essential for proper brain function. We found that Rhes, a small GTPase, modulates iron trafficking in the brain. Rhes is induced by thyroid hormone, which plays an important role in neurodevelopment. Our project harnesses multiple biochemical and cellular techniques to gain mechanistic insight into how Rhes regulates iron homeostasis and contributes to the neuronal function, which will suggest novel avenues for therapeutic intervention.
|Carlson, G C; Lin, R E; Chen, Y et al. (2016) Dexras1 a unique ras-GTPase interacts with NMDA receptor activity and provides a novel dissociation between anxiety, working memory and sensory gating. Neuroscience 322:408-15|
|Chen, Yong; Bang, Sookhee; McMullen, Mary F et al. (2016) Neuronal Activity-Induced Sterol Regulatory Element Binding Protein-1 (SREBP1) is Disrupted in Dysbindin-Null Mice-Potential Link to Cognitive Impairment in Schizophrenia. Mol Neurobiol :|
|Ghosh, Mausam; Lane, Meredith; Krizman, Elizabeth et al. (2016) The transcription factor Pax6 contributes to the induction of GLT-1 expression in astrocytes through an interaction with a distal enhancer element. J Neurochem 136:262-75|
|Opladen, Thomas; Lindner, Martin; Das, Anibh M et al. (2016) In vivo monitoring of urea cycle activity with (13)C-acetate as a tracer of ureagenesis. Mol Genet Metab 117:19-26|
|Port, Russell G; Gaetz, William; Bloy, Luke et al. (2016) Exploring the relationship between cortical GABA concentrations, auditory gamma-band responses and development in ASD: Evidence for an altered maturational trajectory in ASD. Autism Res :|
|White, Rachel S; Bhattacharya, Anup K; Chen, Yong et al. (2016) Lysosomal iron modulates NMDA receptor-mediated excitation via small GTPase, Dexras1. Mol Brain 9:38|
|Edgar, J Christopher; Fisk 4th, Charles L; Liu, Song et al. (2016) Translating Adult Electrophysiology Findings to Younger Patient Populations: Difficulty Measuring 40-Hz Auditory Steady-State Responses in Typically Developing Children and Children with Autism Spectrum Disorder. Dev Neurosci 38:1-14|
|Port, Russell G; Edgar, J Christopher; Ku, Matthew et al. (2016) Maturation of auditory neural processes in autism spectrum disorder - A longitudinal MEG study. Neuroimage Clin 11:566-77|
|Antezana, Ligia; Mosner, Maya G; Troiani, Vanessa et al. (2016) Social-Emotional Inhibition of Return in Children with Autism Spectrum Disorder Versus Typical Development. J Autism Dev Disord 46:1236-46|
|Mlynarski, Elisabeth E; Xie, Michael; Taylor, Deanne et al. (2016) Rare copy number variants and congenital heart defects in the 22q11.2 deletion syndrome. Hum Genet 135:273-85|
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