Impact of Zinc Transport Mechanisms on Embryonic and Brain Development

Willekens, Jérèmy; Runnels, Loren W.

doi:10.3390/nu14122526

Cited by 18 publications

(11 citation statements)

References 427 publications

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“…Upon close inspection of our RNA-seq data, we identified 5 down-regulated genes that are directly involved in different aspects of neurodevelopment. For instance, genetic variants of SLC30A2 have been associated with zinc deficiency, which affects brain development and produces neurobehavioral impairments [ 111 ]. TUBB2B ’s has been implicated in polymicrogyria, a condition, characterized by increased folding of cerebral cortex and cortical layer malformations [ 112 ].…”

Section: Discussionmentioning

confidence: 99%

The ortholog of human ssDNA-binding protein SSBP3 influences neurodevelopment and autism-like behaviors in Drosophila melanogaster

et al. 2023

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1p32.3 microdeletion/duplication is implicated in many neurodevelopmental disorders-like phenotypes such as developmental delay, intellectual disability, autism, macro/microcephaly, and dysmorphic features. The 1p32.3 chromosomal region harbors several genes critical for development; however, their validation and characterization remain inadequate. One such gene is the single-stranded DNA-binding protein 3 (SSBP3) and its Drosophila melanogaster ortholog is called sequence-specific single-stranded DNA-binding protein (Ssdp). Here, we investigated consequences of Ssdp manipulations on neurodevelopment, gene expression, physiological function, and autism-associated behaviors using Drosophila models. We found that SSBP3 and Ssdp are expressed in excitatory neurons in the brain. Ssdp overexpression caused morphological alterations in Drosophila wing, mechanosensory bristles, and head. Ssdp manipulations also affected the neuropil brain volume and glial cell number in larvae and adult flies. Moreover, Ssdp overexpression led to differential changes in synaptic density in specific brain regions. We observed decreased levels of armadillo in the heads of Ssdp overexpressing flies, as well as a decrease in armadillo and wingless expression in the larval wing discs, implicating the involvement of the canonical Wnt signaling pathway in Ssdp functionality. RNA sequencing revealed perturbation of oxidative stress-related pathways in heads of Ssdp overexpressing flies. Furthermore, Ssdp overexpressing brains showed enhanced reactive oxygen species (ROS), altered neuronal mitochondrial morphology, and up-regulated fission and fusion genes. Flies with elevated levels of Ssdp exhibited heightened anxiety-like behavior, altered decisiveness, defective sensory perception and habituation, abnormal social interaction, and feeding defects, which were phenocopied in the pan-neuronal Ssdp knockdown flies, suggesting that Ssdp is dosage sensitive. Partial rescue of behavioral defects was observed upon normalization of Ssdp levels. Notably, Ssdp knockdown exclusively in adult flies did not produce behavioral and functional defects. Finally, we show that optogenetic manipulation of Ssdp-expressing neurons altered autism-associated behaviors. Collectively, our findings provide evidence that Ssdp, a dosage-sensitive gene in the 1p32.3 chromosomal region, is associated with various anatomical, physiological, and behavioral defects, which may be relevant to neurodevelopmental disorders like autism. Our study proposes SSBP3 as a critical gene in the 1p32.3 microdeletion/duplication genomic region and sheds light on the functional role of Ssdp in neurodevelopmental processes in Drosophila.

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Section: Discussionmentioning

confidence: 99%

The ortholog of human ssDNA-binding protein SSBP3 influences neurodevelopment and autism-like behaviors in Drosophila melanogaster

et al. 2023

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“…After the blood passes through the sinusoids, it is directed to the central vein, then hepatic veins and eventually the systemic circulation [ 98 ]. From the systemic circulation, zinc ions are transported to various body tissues such as the in brain, muscle, and bone [ 100 ] (Fig. 1 ).…”

Section: Zinc Uptake Absorption and Regulators Of Its Bioavailabilitymentioning

confidence: 99%

Role of zinc in health and disease

Stiles,

Ferrao,

Mehta

2024

Clin Exp Med

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This review provides a concise overview of the cellular and clinical aspects of the role of zinc, an essential micronutrient, in human physiology and discusses zinc-related pathological states. Zinc cannot be stored in significant amounts, so regular dietary intake is essential. ZIP4 and/or ZnT5B transport dietary zinc ions from the duodenum into the enterocyte, ZnT1 transports zinc ions from the enterocyte into the circulation, and ZnT5B (bidirectional zinc transporter) facilitates endogenous zinc secretion into the intestinal lumen. Putative promoters of zinc absorption that increase its bioavailability include amino acids released from protein digestion and citrate, whereas dietary phytates, casein and calcium can reduce zinc bioavailability. In circulation, 70% of zinc is bound to albumin, and the majority in the body is found in skeletal muscle and bone. Zinc excretion is via faeces (predominantly), urine, sweat, menstrual flow and semen. Excessive zinc intake can inhibit the absorption of copper and iron, leading to copper deficiency and anaemia, respectively. Zinc toxicity can adversely affect the lipid profile and immune system, and its treatment depends on the mode of zinc acquisition. Acquired zinc deficiency usually presents later in life alongside risk factors like malabsorption syndromes, but medications like diuretics and angiotensin-receptor blockers can also cause zinc deficiency. Inherited zinc deficiency condition acrodermatitis enteropathica, which occurs due to mutation in the SLC39A4 gene (encoding ZIP4), presents from birth. Treatment involves zinc supplementation via zinc gluconate, zinc sulphate or zinc chloride. Notably, oral zinc supplementation may decrease the absorption of drugs like ciprofloxacin, doxycycline and risedronate.

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“…SLC30A9 (first known as HUEL) encodes the zinc transporter protein 9 (ZnT9), which is involved in zinc transport and homeostasis in the endoplasmic reticulum [69]. Whilst the function of the protein is not fully understood, a 3 nt familial deletion (c.1047_1049delGCA) in the highly conserved cation efflux domain (CED) has been recorded to result in changes to protein structure, intracellular zinc levels and intellectual disability [70,71]. Critically, we identified and validated a novel exon (Tx3-9a:73 nt) within this CED providing evidence that this region may be alternatively spliced more commonly than previously understood, potentially impacting protein function [69].…”

Section: Novel Rna Isoforms In Neuropsychiatric Disordersmentioning

confidence: 99%

Long-read sequencing reveals the RNA isoform repertoire of neuropsychiatric risk genes in human brain

Paoli-Iseppi,

Joshi,

Gleeson

et al. 2024

Preprint

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Neuropsychiatric disorders are highly complex conditions and the risk of developing a disorder has been tied to hundreds of genomic variants that alter the expression and/or products (isoforms) made by risk genes. However, how these genes contribute to disease risk and onset through altered expression and RNA splicing is not well understood. Here we show our current understanding of gene isoforms is far from complete and reveal the precise splicing profiles of neuropsychiatric disorder risk genes. Combining our new bioinformatic pipeline IsoLamp with nanopore long-read amplicon sequencing, we deeply profiled the RNA isoform repertoire of 31 high-confidence neuropsychiatric disorder risk genes in human brain. We show most risk genes are more complex than previously reported, identifying 440 novel isoforms and 28 novel exons, including isoforms which alter protein domains, and genes such as ATG13 and GATAD2A where most expression was from previously undiscovered isoforms. The greatest isoform diversity was present in the schizophrenia risk gene ITIH4. Mass spectrometry of brain protein isolates confirmed translation of a novel exon skipping event in ITIH4, suggesting a new regulatory mechanism for this gene in brain. Our results emphasize the widespread presence of previously undetected RNA and protein isoforms in brain and provide an effective approach to address this knowledge gap. Uncovering the isoform repertoire of neuropsychiatric risk genes will underpin future analyses of the functional impact these isoforms have on neuropsychiatric disorders, enabling the translation of genomic findings into a pathophysiological understanding of disease.

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Impact of Zinc Transport Mechanisms on Embryonic and Brain Development

Cited by 18 publications

References 427 publications

The ortholog of human ssDNA-binding protein SSBP3 influences neurodevelopment and autism-like behaviors in Drosophila melanogaster

The ortholog of human ssDNA-binding protein SSBP3 influences neurodevelopment and autism-like behaviors in Drosophila melanogaster

Role of zinc in health and disease

Long-read sequencing reveals the RNA isoform repertoire of neuropsychiatric risk genes in human brain

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