Dataset Information

Cellular Iron Deficiency Disrupts Thyroid Hormone Regulated Gene Expression in Developing Hippocampal Neurons.

ABSTRACT:

Background

Developing neurons have high thyroid hormone and iron requirements to support their metabolism and growth. Early-life iron and thyroid hormone deficiencies are prevalent, often coexist, and increase the risk of permanently impaired neurobehavioral function in children. Early-life dietary iron deficiency reduces thyroid hormone levels and impairs thyroid hormone-responsive gene expression in the neonatal rat brain.

Objective

This study determined whether neuronal-specific iron deficiency alters thyroid hormone-regulated gene expression in developing neurons.

Methods

Iron deficiency was induced in primary mouse embryonic hippocampal neuron cultures with the iron chelator deferoxamine (DFO) beginning at 3 days in vitro (DIV). At 11DIV and 18DIV, mRNA levels for thyroid hormone-regulated genes indexing thyroid hormone homeostasis ( Hr , Crym , Dio2 , Slco1c1 , Slc16a2 ) and neurodevelopment ( Nrgn , Pvalb , Klf9 ) were quantified. To assess the effect of iron repletion, DFO was removed at 14DIV from a subset of DFO-treated cultures and gene expression and ATP levels were quantified at 21DIV.

Results

At 11DIV and 18DIV, neuronal iron deficiency decreased Nrgn, Pvalb, and Crym , and by 18DIV, Slc16a2, Slco1c1, Dio2, and Hr were increased; collectively suggesting cellular sensing of a functionally abnormal thyroid hormone state. Dimensionality reduction with Principal Component Analysis (PCA) reveals that thyroid hormone homeostatic genes strongly correlate with and predict iron status ( Tfr1 mRNA). Iron repletion from 14-21DIV restored neurodevelopmental genes, but not all thyroid hormone homeostatic genes, and ATP concentrations remained significantly altered. PCA clustering suggests that cultures replete with iron maintain a gene expression signature indicative of previous iron deficiency.

Conclusions

These novel findings suggest there is an intracellular mechanism coordinating cellular iron/thyroid hormone activities. We speculate this is a part of homeostatic response to match neuronal energy production and growth signaling for these important metabolic regulators. However, iron deficiency may cause permanent deficits in thyroid hormone-dependent neurodevelopmental processes even after recovery from iron deficiency.

SUBMITTER: Monko TR

PROVIDER: S-EPMC10312787 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Publications

Cellular Iron Deficiency Disrupts Thyroid Hormone Regulated Gene Expression in Developing Hippocampal Neurons.

Monko Timothy R TR Tripp Emma H EH Burr Sierra E SE Gunderson Karina N KN Lanier Lorene M LM Georgieff Michael K MK Bastian Thomas W TW

bioRxiv : the preprint server for biology 20230617

<h4>Background</h4>Developing neurons have high thyroid hormone and iron requirements to support their metabolism and growth. Early-life iron and thyroid hormone deficiencies are prevalent, often coexist, and increase the risk of permanently impaired neurobehavioral function in children. Early-life dietary iron deficiency reduces thyroid hormone levels and impairs thyroid hormone-responsive gene expression in the neonatal rat brain.<h4>Objective</h4>This study determined whether neuronal-specifi ...[more]

PMID: 37398002

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Project description:BackgroundDeveloping neurons have high thyroid hormone and iron requirements to support their metabolically demanding growth. Early-life iron and thyroid-hormone deficiencies are prevalent and often coexist, and each independently increases risk of permanently impaired neurobehavioral function in children. Early-life dietary iron deficiency reduces thyroid-hormone concentrations and impairs thyroid hormone-responsive gene expression in the neonatal rat brain, but it is unclear whether the effect is cell-intrinsic.ObjectivesThis study determined whether neuronal-specific iron deficiency alters thyroid hormone-regulated gene expression in developing neurons.MethodsIron deficiency was induced in primary mouse embryonic hippocampal neuron cultures with the iron chelator deferoxamine (DFO) beginning at 3 d in vitro (DIV). At 11DIV and 18DIV, thyroid hormone-regulated gene messenger ribonucleic acid (mRNA)concentrations indexing thyroid hormone homeostasis (Hairless, mu-crystallin, Type II deiodinase, solute carrier family member 1c1, and solute carrier family member 16a2) and neurodevelopment (neurogranin, Parvalbumin, and Krüppel-like factor 9) were quantified. To assess the effect of iron repletion, DFO was removed at 14DIV from a subset of DFO-treated cultures, and gene expression and adenosine 5'-triphosphate (ATP) concentrations were quantified at 21DIV.ResultsAt 11DIV and 18DIV, neuronal iron deficiency decreased neurogranin, Parvalbumin, and mu-crystallin, and by 18DIV, solute carrier family member 16a2, solute carrier family member 1c1, Type II deiodinase, and Hairless were increased, suggesting cellular sensing of a functionally abnormal thyroid hormone state. Dimensionality reduction with Principal component analysis reveals that thyroid hormone homeostatic genes strongly correlate with and predict iron status. Iron repletion from 14-21DIV did not restore ATP concentration, and Principal component analysis suggests that, after iron repletion, cultures maintain a gene expression signature indicative of previous iron deficiency.ConclusionsThese novel findings suggest there is an intracellular mechanism coordinating cellular iron/thyroid hormone activities. We speculate this is a part of the homeostatic response to acutely match neuronal energy production and growth signaling. However, the adaptation to iron deficiency may cause permanent deficits in thyroid hormone-dependent neurodevelopmental processes even after recovery from iron deficiency.

Project description:Iron deficiency (ID), with and without anemia, affects an estimated 2 billion people worldwide. ID is particularly deleterious during early-life brain development, leading to long-term neurological impairments including deficits in hippocampus-mediated learning and memory. Neonatal rats with fetal/neonatal ID anemia (IDA) have shorter hippocampal CA1 apical dendrites with disorganized branching. ID-induced dendritic structural abnormalities persist into adulthood despite normalization of the iron status. However, the specific developmental effects of neuronal iron loss on hippocampal neuron dendrite growth and branching are unknown. Embryonic hippocampal neuron cultures were chronically treated with deferoxamine (DFO, an iron chelator) beginning at 3 days in vitro (DIV). Levels of mRNA for Tfr1 and Slc11a2, iron-responsive genes involved in iron uptake, were significantly elevated in DFO-treated cultures at 11DIV and 18DIV, indicating a degree of neuronal ID similar to that seen in rodent ID models. DFO treatment decreased mRNA levels for genes indexing dendritic and synaptic development (i.e. BdnfVI,Camk2a,Vamp1,Psd95,Cfl1, Pfn1,Pfn2, and Gda) and mitochondrial function (i.e. Ucp2,Pink1, and Cox6a1). At 18DIV, DFO reduced key aspects of energy metabolism including basal respiration, maximal respiration, spare respiratory capacity, ATP production, and glycolytic rate, capacity, and reserve. Sholl analysis revealed a significant decrease in distal dendritic complexity in DFO-treated neurons at both 11DIV and 18DIV. At 11DIV, the length of primary dendrites and the number and length of branches in DFO-treated neurons were reduced. By 18DIV, partial recovery of the dendritic branch number in DFO-treated neurons was counteracted by a significant reduction in the number and length of primary dendrites and the length of branches. Our findings suggest that early neuronal iron loss, at least partially driven through altered mitochondrial function and neuronal energy metabolism, is responsible for the effects of fetal/neonatal ID and IDA on hippocampal neuron dendritic and synaptic maturation. Impairments in these neurodevelopmental processes likely underlie the negative impact of early life ID and IDA on hippocampus-mediated learning and memory.

Project description:BackgroundFetal-neonatal iron deficiency causes learning/memory deficits that persist after iron repletion. Simplified hippocampal neuron dendrite structure is a key mechanism underlying these long-term impairments. Early life choline supplementation, with postnatal iron repletion, improves learning/memory performance in formerly iron-deficient (ID) rats.ObjectivesTo understand how choline improves iron deficiency-induced hippocampal dysfunction, we hypothesized that direct choline supplementation of ID hippocampal neurons may restore cellular energy production and dendrite structure.MethodsEmbryonic mouse hippocampal neuron cultures were made ID with 9 μM deferoxamine beginning at 3 d in vitro (DIV). At 11 DIV, iron repletion (i.e., deferoxamine removal) was performed on a subset of ID cultures. These neuron cultures and iron-sufficient (IS) control cultures were treated with 30 μM choline (or vehicle) between 11 and 18 DIV. At 18 DIV, the independent and combined effects of iron and choline treatments (2-factor ANOVA) on neuronal dendrite numbers, lengths, and overall complexity and mitochondrial respiration and glycolysis were analyzed.ResultsCholine treatment of ID neurons (ID + Cho) significantly increased overall dendrite complexity (150, 160, 180, and 210 μm from the soma) compared with untreated ID neurons to a level of complexity that was no longer significantly different from IS neurons. The average and total length of primary dendrites in ID + Cho neurons were significantly increased by ∼15% compared with ID neurons, indicating choline stimulation of dendrite growth. Measures of mitochondrial respiration, glycolysis, and ATP production rates were not significantly altered in ID + Cho neurons compared with ID neurons, remaining significantly reduced compared with IS neurons. Iron repletion significantly improved mitochondrial respiration, ATP production rates, overall dendrite complexity (100-180 μm from the soma), and dendrite and branch lengths compared with untreated ID neurons.ConclusionsBecause choline partially restores dendrite structure in ID neurons without iron repletion, it may have therapeutic potential when iron treatment is not possible or advisable. Choline's mechanism in ID neurons requires further investigation.

Dataset Information

Cellular Iron Deficiency Disrupts Thyroid Hormone Regulated Gene Expression in Developing Hippocampal Neurons.

Background

Objective

Methods

Results

Conclusions

Publications

Cellular Iron Deficiency Disrupts Thyroid Hormone Regulated Gene Expression in Developing Hippocampal Neurons.

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