Sonic Hedgehog-Gli1 Signaling and Cellular Retinoic Acid Binding Protein 1 Gene Regulation in Motor Neuron Differentiation and Diseases

Lin, Yu Wen; Lin, Yi; Nhieu, Jennifer; Zhang, Xiaoyin; Li, Wei

doi:10.3390/ijms21114125

Cited by 21 publications

(26 citation statements)

References 41 publications

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“…The D3 dopamine receptor plays a role in clinical antipsychotic response [ 36 ]. Crabp1 encodes a protein that binds retinoic acid, which is involved in the differentiation of neurons [ 37 , 38 , 39 ]. Of the 149 genes common to two or more datasets, most were shared between AM and mPFC ( n = 72), NA and mPFC ( n = 63), and AM and NAc ( n = 12).…”

Section: Resultsmentioning

confidence: 99%

Meta-Analysis of Brain Gene Expression Data from Mouse Model Studies of Maternal Immune Activation Using Poly(I:C)

Laighneach

Desbonnet

Kelly

et al. 2021

Genes

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Maternal immune activation (MIA) is a known risk factor for schizophrenia (SCZ) and autism spectrum disorder (ASD) and is often modelled in animal studies in order to study the effect of prenatal infection on brain function including behaviour and gene expression. Although the effect of MIA on gene expression are highly heterogeneous, combining data from multiple gene expression studies in a robust method may shed light on the true underlying biological effects caused by MIA and this could inform studies of SCZ and ASD. This study combined four RNA-seq and microarray datasets in an overlap analysis and ranked meta-analysis in order to investigate genes, pathways and cell types dysregulated in the MIA mouse models. Genes linked to SCZ and ASD and crucial in neurodevelopmental processes including neural tube folding, regulation of cellular stress and neuronal/glial cell differentiation were among the most consistently dysregulated in these ranked analyses. Gene ontologies including K+ ion channel function, neuron and glial cell differentiation, synaptic structure, axonal outgrowth, cilia function and lipid metabolism were also strongly implicated. Single-cell analysis identified excitatory and inhibitory cell types in the cortex, hippocampus and striatum that may be affected by MIA and are also enriched for genes associated with SCZ, ASD and cognitive phenotypes. This points to the cellular location of molecular mechanisms that may be consistent between the MIA model and neurodevelopmental disease, improving our understanding of its utility to study prenatal infection as an environmental stressor.

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Section: Resultsmentioning

confidence: 99%

Meta-Analysis of Brain Gene Expression Data from Mouse Model Studies of Maternal Immune Activation Using Poly(I:C)

Laighneach

Desbonnet

Kelly

et al. 2021

Genes

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“…SHH exerts a critical function on promoting cell proliferation and differentiation, maintaining the integrity of blood–brain barrier, and protecting cells from oxidative stress ( Xia et al, 2012 ). There is evidence that SHH exerts a key function on ALS ( Lin et al, 2020 ). A study found that the decrease in the expression of cellular retinoic acid–binding protein 1 (CRABP1) is correlated with motor neuron degeneration ( Lin et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

“…There is evidence that SHH exerts a key function on ALS ( Lin et al, 2020 ). A study found that the decrease in the expression of cellular retinoic acid–binding protein 1 (CRABP1) is correlated with motor neuron degeneration ( Lin et al, 2020 ). SHH may elevate CRABP1 expression through mediating GLI1, which involves specific chromatin remodeling ( Lin et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

“…A study found that the decrease in the expression of cellular retinoic acid–binding protein 1 (CRABP1) is correlated with motor neuron degeneration ( Lin et al, 2020 ). SHH may elevate CRABP1 expression through mediating GLI1, which involves specific chromatin remodeling ( Lin et al, 2020 ). Because purmorphamine acts on Smoothened, downstream of SHH and its receptor Patched, the inhibitory action is downstream of Smoothened ( Drannik et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

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The Role of Sonic Hedgehog Pathway in the Development of the Central Nervous System and Aging-Related Neurodegenerative Diseases

Yang

Yan

Sun

2021

Front. Mol. Biosci.

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The Sonic hedgehog (SHH) pathway affects neurogenesis and neural patterning during the development of the central nervous system. Dysregulation of the SHH pathway in the brain contributes to aging-related neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. At present, the SHH signaling pathway can be divided into the canonical signaling pathway and non-canonical signaling pathway, which directly or indirectly mediates other related pathways involved in the development of neurodegenerative diseases. Hence, an in-depth knowledge of the SHH signaling pathway may open an avenue of possibilities for the treatment of neurodegenerative diseases. Here, we summarize the role and mechanism of the SHH signaling pathway in the development of the central nervous system and aging-related neurodegenerative diseases. In this review, we will also highlight the potential of the SHH pathway as a therapeutic target for treating neurodegenerative diseases.

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“…It is known that RA can also directly elicit activities to modulate cytosolic signaling [14][15][16][17][18][19][20], mediated by a speci c, cytosolic RA signaling protein called Cellular retinoic acid-binding protein I (Crabp1) [21]. Our previous studies have shown that Crabp1 levels are altered in certain pathological conditions such as under neuronal stress or neuroin ammation [16,22], and in metabolic diseases and heart failure [23], suggesting a relevance to diseases. This current study reports a new functional role of Crabp1, that it regulates intercellular communication to impact on system wide homeostasis by modulating exosome secretion.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Exosome Secretion by Cellular Retinoic Acid Binding Protein 1 Contributes to Systemic Anti-inflammation

Lin

Nhieu

Wei

et al. 2021

Preprint

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Background: Intercellular communications are important for maintaining normal physiological processes. An important intercellular communication is mediated by the exchange of membrane-enclosed extracellular vesicles. Among various vesicles, exosomes can be detected in a wide variety of biological systems, but the regulation and biological implication of exosome secretion/uptake remains largely unclear.Methods: Cellular retinoic acid (RA) binding protein 1 (Crabp1) knockout (CKO) mice were used for in vivo studies. Extracellular exosomes were monitored in CKO mice and relevant cell cultures including embryonic stem cell (CJ7), macrophage (Raw 264.7) and hippocampal cell (HT22) using Western blot and flow cytometry. Receptor Interacting Protein 140 (RIP140) was depleted by Crispr/Cas9-mediated gene editing. Anti-inflammatory maker was analyzed using qRT-PCR. Clinical relevance was accessed by mining multiple clinical datasets. Results: This study uncovers Crabp1 as a negative regulator of exosome secretion from neurons. Specifically, RIP140, a pro-inflammatory regulator, can be transferred from neurons, via Crabp1-regulated exosome secretion, into macrophages to promote their inflammatory polarization. Consistently, CKO mice, defected in the negative control of exosome secretion, have significantly elevated RIP140-containing exosomes in their blood and cerebrospinal fluid, and exhibit an increased vulnerability to systemic inflammation. Clinical relevance of this pathway is supported by patients’ data of multiple inflammatory diseases. Further, the action of Crabp1 in regulating exosome secretion involves its ligand and is mediated by its downstream target, the MAPK signaling pathway.Conclusions: This study presents the first evidence for the regulation of exosome secretion, which mediates intercellular communication, by RA-Crabp1 signaling. This novel mechanism can contribute to the control of systemic inflammation by transferring an inflammatory regulator, RIP140, between cells. This represents a new mechanism of vitamin A action that can modulate the homeostasis of system-wide innate immunity without involving gene regulation.

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Sonic Hedgehog-Gli1 Signaling and Cellular Retinoic Acid Binding Protein 1 Gene Regulation in Motor Neuron Differentiation and Diseases

Cited by 21 publications

References 41 publications

Meta-Analysis of Brain Gene Expression Data from Mouse Model Studies of Maternal Immune Activation Using Poly(I:C)

Meta-Analysis of Brain Gene Expression Data from Mouse Model Studies of Maternal Immune Activation Using Poly(I:C)

The Role of Sonic Hedgehog Pathway in the Development of the Central Nervous System and Aging-Related Neurodegenerative Diseases

Regulation of Exosome Secretion by Cellular Retinoic Acid Binding Protein 1 Contributes to Systemic Anti-inflammation

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