Sonic hedgehog-gli1 signaling and cellular retinoic acid binding protein 1 gene regulation in motor neuron differentiation and diseases

Yu Lung Lin, Yi Wei Lin, Jennifer Nhieu, Xiaoyin Zhang, Li Na Wei

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number4125
Pages (from-to)1-15
Number of pages15
JournalInternational journal of molecular sciences
Volume21
Issue number11
DOIs
StatePublished - Jun 1 2020

Bibliographical note

Funding Information:
Funding: This work is supported by NIH grants DK54733, DK60521, and the Dean’s Commitment and the Distinguished McKnight Professorship of University of Minnesota to LN.W. J.N. is supported by 1F31DK123999.

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • ALS
  • CRABP1
  • Chromatin remodeling
  • Gli
  • Motor neuron
  • Retinoic acid
  • SMA
  • Sonic hedgehog

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