Identification and Analysis of ZIC-Related Genes in Cerebellum of Autism Spectrum Disorders

Introduction

 

Autism spectrum disorder (ASD) is a complex condition that affects how people communicate, interact, and behave. It is influenced by many genetic and environmental factors, but the exact causes are still unclear. One of the genes that may be involved in ASD is the ZIC gene family, which regulates the development of the brain, especially the cerebellum. The cerebellum is a part of the brain that controls movement, coordination, and learning. Previous studies have shown that the cerebellum is abnormal in some people with ASD, and that mice with mutations in ZIC genes exhibit ASD-like behaviors.

 

In this paper, the authors used bioinformatics tools to analyze the expression and function of ZIC genes in the cerebellum of people with ASD. They also compared the results with those of a mouse model of ASD induced by maternal immune activation (MIA), which mimics the effects of infection or inflammation during pregnancy.

 

ZIC Genes Are Associated with ASD Risk Genes and Neurodevelopmental Disorders

 

The authors first searched for the association of ZIC genes with ASD risk genes from the Simons Foundation Autism Research Initiative (SFARI) database, which collects and curates information on genes linked to ASD. They found that ZIC1, ZIC2, and ZIC3 were associated with several ASD risk genes, such as CHD8, NRXN1, and SHANK3. These genes are involved in the formation and function of synapses, the connections between neurons.

 

They also searched for the expression of ZIC genes in different brain regions using the Human Protein Atlas (HPA) database, which provides data on the location and abundance of proteins in human tissues. They found that ZIC1, ZIC2, and ZIC3 were highly expressed in the cerebellum, as well as in other brain regions related to ASD, such as the hippocampus, the amygdala, and the cortex.

 

These results suggest that ZIC genes may play a role in ASD by affecting the development and function of the cerebellum and other brain regions.

ZIC Genes Affect the Cerebellar Environment and Neuronal Development in ASD

 

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The authors then used a dataset of gene expression profiles from the cerebellum of 83 ASD patients and 88 controls to investigate the co-expression and function of ZIC genes and their related genes. They identified two groups of genes that were positively or negatively correlated with ZIC1, ZIC2, and ZIC3, and performed pathway analysis and diagnostic accuracy analysis on them.

 

They found that the genes positively correlated with ZIC genes were enriched in pathways related to neuronal development, such as axon guidance, neurotrophin signaling, and synaptic vesicle cycle. These pathways are essential for the formation and maintenance of neural circuits. They also found that some of these genes, such as OLFM3, SLC27A4, GRB2, TMED1, NR2F1, and STRBP, had good diagnostic accuracy for ASD, meaning that they could distinguish ASD patients from controls based on their expression levels.

 

They also found that the genes negatively correlated with ZIC genes were enriched in pathways related to the cerebellar environment, such as immune response, astrocyte function, and endothelial cell function. These pathways are important for the regulation of inflammation, blood-brain barrier, and nutrient supply in the brain. They also found that some of these genes, such as CCL2, CXCL10, GFAP, AQP4, and CDH5, had good diagnostic accuracy for ASD.

 

These results suggest that ZIC genes may affect the cerebellar environment and neuronal development in ASD, and that their related genes may serve as potential biomarkers for ASD diagnosis.

 

ZIC Genes Are Altered in a Mouse Model of ASD

 

The authors also tested the expression of ZIC genes and their related genes in a mouse model of ASD induced by MIA. They found that Zic3 and Nr2f1, two of the genes positively correlated with ZIC genes in humans, were significantly downregulated in the cerebellum of MIA mice compared to controls. This indicates that ZIC genes may be affected by maternal immune activation, which is a risk factor for ASD.

 

Conclusion

 

This paper provides evidence that ZIC genes are involved in ASD pathogenesis by influencing the cerebellar environment and neuronal development. It also identifies some of the genes that are co-expressed with ZIC genes and have good diagnostic accuracy for ASD. These genes may serve as potential targets for early and accurate prediction of ASD. The paper also demonstrates that ZIC genes are altered in a mouse model of ASD, which may help to understand the molecular mechanisms of ASD.

 

Faq

What is the difference between gene expression and gene function?

Gene expression is the process by which the information encoded in a gene is converted into a product, such as a protein or an RNA molecule. Gene expression can be measured by the level and location of the gene product in a given sample. Gene function is the role and effect of the gene product on the biological processes, molecular functions, cellular components, and pathways in a given system. Gene function can be inferred by the changes in the system caused by the alteration or manipulation of the gene product.

 

What are ZIC genes and what do they do?

ZIC genes are a family of genes that encode zinc finger proteins, which are transcription factors that regulate gene expression. ZIC genes are involved in various aspects of embryonic development, especially the formation of the neural tube and the cerebellum. ZIC genes also play a role in adult brain function, such as learning and memory.

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How many ZIC genes are there and what are their names?

There are five ZIC genes in humans: ZIC1, ZIC2, ZIC3, ZIC4, and ZIC5. They are located on different chromosomes and have different functions and interactions. ZIC1, ZIC2, and ZIC3 are more closely related to each other than to ZIC4 and ZIC5.

 

What is the cerebellum and what does it do?

The cerebellum is a part of the brain that is located at the back of the skull, below the cerebrum. The cerebellum is responsible for coordinating movement, balance, posture, and motor learning. It also contributes to cognitive functions, such as attention, language, and emotion.

 

How is the cerebellum related to autism spectrum disorder (ASD)?

The cerebellum is one of the brain regions that is abnormal in some people with ASD. Studies have shown that the cerebellum is smaller, has fewer neurons, and has altered connectivity in ASD. These abnormalities may affect the cerebellar functions and impair the communication and integration with other brain regions. The cerebellum may also influence the development of other brain regions during early life, and thus affect the risk of ASD.

 

What is maternal immune activation (MIA) and how does it affect ASD?

Maternal immune activation (MIA) is a condition where the mother’s immune system is activated by infection or inflammation during pregnancy. MIA can cause changes in the fetal brain development and increase the risk of neurodevelopmental disorders, such as ASD, in the offspring. MIA can also alter the expression of genes that are involved in brain development and function, such as ZIC genes.

 

What are some of the genes that are positively correlated with ZIC genes and have good diagnostic accuracy for ASD?

 

Some of the genes that are positively correlated with ZIC genes and have good diagnostic accuracy for ASD are:

  • OLFM3: a gene that encodes a protein that modulates the activity of synaptic adhesion molecules and promotes synapse formation and plasticity.
  • SLC27A4: a gene that encodes a protein that transports fatty acids across the cell membrane and regulates lipid metabolism and signaling.
  • GRB2: a gene that encodes a protein that mediates the activation of various signaling pathways, such as the Ras-MAPK pathway, which is involved in neuronal differentiation and survival.
  • TMED1: a gene that encodes a protein that is involved in the trafficking and sorting of membrane proteins, such as receptors and ion channels.
  • NR2F1: a gene that encodes a protein that is a transcription factor that regulates the expression of genes involved in neuronal development and function, such as ZIC genes.
  • STRBP: a gene that encodes a protein that binds to RNA and DNA and regulates the stability and translation of mRNA.

 

What are some of the genes that are negatively correlated with ZIC genes and have good diagnostic accuracy for ASD?

 

Some of the genes that are negatively correlated with ZIC genes and have good diagnostic accuracy for ASD are:

  • CCL2: a gene that encodes a protein that is a chemokine, which is a type of cytokine that attracts and activates immune cells, such as macrophages and T cells.
  • CXCL10: a gene that encodes a protein that is also a chemokine, which is involved in the inflammatory response and the recruitment of immune cells, such as monocytes and NK cells.
  • GFAP: a gene that encodes a protein that is a component of the intermediate filaments of astrocytes, which are a type of glial cell that support and modulate neuronal activity.
  • AQP4: a gene that encodes a protein that is a water channel that regulates the movement of water across the cell membrane of astrocytes and endothelial cells, which are the cells that line the blood vessels.
  • CDH5: a gene that encodes a protein that is a cadherin, which is a type of adhesion molecule that mediates the interaction and junction of endothelial cells and maintains the integrity of the blood-brain barrier.
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How are the genes that are positively correlated with ZIC genes related to neuronal development in ASD?

 

The genes that are positively correlated with ZIC genes are related to neuronal development in ASD by affecting the processes that are essential for the formation and maintenance of neural circuits, such as axon guidance, neurotrophin signaling, and synaptic vesicle cycle. These processes are responsible for the growth and direction of axons, the survival and differentiation of neurons, and the release and recycling of neurotransmitters, respectively. These processes are impaired in ASD, leading to abnormal connectivity and function of the brain.

 

How are the genes that are negatively correlated with ZIC genes related to the cerebellar environment in ASD?

 

The genes that are negatively correlated with ZIC genes are related to the cerebellar environment in ASD by affecting the processes that are important for the regulation of inflammation, blood-brain barrier, and nutrient supply in the brain, such as immune response, astrocyte function, and endothelial cell function. These processes are responsible for the protection and modulation of the brain from harmful stimuli, such as pathogens and toxins, and the provision of oxygen and glucose to the brain, respectively. These processes are altered in ASD, leading to increased inflammation, impaired blood-brain barrier, and reduced nutrient supply in the brain.

What are the effects of ZIC gene mutations on ASD?

ZIC gene mutations can cause various syndromes and disorders that are associated with ASD, such as Dandy-Walker malformation, holoprosencephaly, heterotaxy, and Joubert syndrome. These syndromes and disorders are characterized by structural and functional abnormalities of the brain and other organs, such as the cerebellum, the forebrain, the heart, and the kidneys. ZIC gene mutations can also affect the expression and function of other genes that are involved in ASD, such as SHANK3, NRXN1, and CHD8, and thus contribute to the pathogenesis of ASD.

 

What are the similarities and differences between ZIC genes and other genes that are involved in ASD?

 

ZIC genes and other genes that are involved in ASD have some similarities and differences in their functions and interactions. Some of the similarities are:

  • They are involved in the development and function of the brain, especially the cerebellum and other brain regions related to ASD, such as the cortex, the hippocampus, and the amygdala.
  • They are associated with ASD risk genes, such as CHD8, NRXN1, and SHANK3, which are involved in the formation and function of synapses, the connections between neurons.
  • They are affected by environmental factors that may contribute to ASD, such as infection, inflammation, stress, and hormones.

 

Some of the differences are:

  • They have different roles and effects on the cerebellar environment and neuronal development in ASD. ZIC genes are positively correlated with genes that are involved in neuronal development, and negatively correlated with genes that are involved in the cerebellar environment. Other genes may have different or opposite correlations with these genes.
  • They have different expression patterns and levels in different brain regions and cell types. ZIC genes are highly expressed in the cerebellum, as well as in other brain regions related to ASD. Other genes may have different or lower expression in these regions.
  • They have different mutations and interactions that may cause or contribute to ASD. ZIC genes have mutations that can cause various syndromes and disorders that are associated with ASD, such as Dandy-Walker malformation, holoprosencephaly, heterotaxy, and Joubert syndrome. Other genes may have different or more common mutations that can cause or contribute to ASD.

 

Source:

https://scholar.google.com/scholar?start=10&q=autism&hl=en&scisbd=1&as_sdt=0,5

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