Abstract
Cellular retinoic acid-binding protein 1 (CRABP1) is highly expressed in motor neurons. Degenerated motor neuron-like MN1 cells are engineered by introducing SODG93A or AR-65Q to model degenerated amyotrophic lateral sclerosis (ALS) or spinal bulbar muscular atrophy neurons. Retinoic acid (RA)/sonic hedgehog (Shh)-induced embryonic stem cells differentiation into motor neurons are employed to study up-regulation of Crabp1 by Shh. In SODG93A or AR-65Q MN1 neurons, CRABP1 level is reduced, revealing a correlation of motor neuron degeneration with Crabp1 down-regulation. Up-regulation of Crabp1 by Shh is mediated by glioma-associated oncogene homolog 1 (Gli1) that binds the Gli target sequence in Crabp1′s neuron-specific regulatory region upstream of minimal promoter. Gli1 binding triggers chromatin juxtaposition with minimal promoter, activating transcription. Motor neuron differentiation and Crabp1 up-regulation are both inhibited by blunting Shh with Gli inhibitor GANT61. Expression data mining of ALS and spinal muscular atrophy (SMA) motor neurons shows reduced CRABP1, coincided with reduction in Shh-Gli1 signaling components. This study reports motor neuron degeneration correlated with down-regulation in Crabp1 and Shh-Gli signaling. Shh-Gli up-regulation of Crabp1 involves specific chromatin remodeling. The physiological and pathological implication of this regulatory pathway in motor neuron degeneration is supported by gene expression data of ALS and SMA patients.
Highlights
Cellular retinoic acid-binding protein 1 (CRABP1) is a highly conserved cytosolic protein for binding retinoic acid (RA) with a high affinity [1]
Given the presence of a conserved Gli binding site in the 200 bps upstream region, and the effects of sonic hedgehog (Shh)/Gli signaling in neurons, this current study focuses on the Shh/Gli pathway to examine how Crabp1 gene is up-regulated in motor neurons and determines whether dysregulation in Crabp1 and Shh/Gli signaling is associated with human diseases of motor neurons
Since Shh-glioma-associated oncogene homolog 1 (Gli1) signaling plays an intimate role in up-regulating Crabp1 and facilitating motor neuron differentiation, we further examined the expression data of Shh-Gli signaling components that are available in the RNA-seq data from the spinal muscular atrophy (SMA) study (GEO Accession: GSE108094) by Rizzo et al, 2019
Summary
Cellular retinoic acid-binding protein 1 (CRABP1) is a highly conserved cytosolic protein for binding retinoic acid (RA) with a high affinity [1]. CRABP1 mRNA is detected in certain tissues/organs such as skin, heart, liver, adipose tissues, and the brain. In developmental stages, it is most highly detected in the developing CNS, especially at the stages of E9.5–E12.5 in mice [4]. The nervous system specificity of Crabp gene during the developmental stages is of most interest. Molecular studies have revealed multiple regulatory regions within a 3 kb sequence upstream of the transcription initiation site (TIS) of the mouse Crabp gene [5,6]
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