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Mirk/Dyrk1B controls ventral spinal cord development via Shh pathway

N Kokkorakis1,2, K Douka1, A Nalmpanti1,3

  • 1Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur Institute, Athens, Greece.

Cellular and Molecular Life Sciences : CMLS
|January 31, 2024
PubMed

Insights

Dual-specificity kinase Dyrk1B suppresses the Sonic hedgehog (Shh)/Gli pathway in the embryonic chick spinal cord. This kinase regulates ventral progenitor and motor neuron development, offering a potential therapeutic target for motor neuron diseases.

Area of Science:

  • Developmental Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • The Sonic hedgehog (Shh)/Gli pathway is crucial for embryonic development, regulating cell proliferation, differentiation, and patterning.
  • Cross-talk between Mirk/Dyrk1B kinase and the Shh/Gli pathway influences physiological and pathological processes.
  • Understanding Dyrk1B's role in spinal cord development is essential for insights into neurodevelopmental disorders and diseases.

Purpose of the Study:

  • To investigate the novel role of Dyrk1B in regulating ventral progenitor and neuron subtypes in the embryonic chick spinal cord.
  • To elucidate the mechanism by which Dyrk1B interacts with the Shh/Gli pathway.
  • To determine the therapeutic potential of targeting Dyrk1B for motor neuron diseases.

Main Methods:

  • In ovo gain- and loss-of-function experiments in embryonic chick spinal cords.
  • Pharmacological inhibition of Dyrk1B kinase activity using AZ191.
  • Assessment of progenitor proliferation, differentiation, and apoptosis.
  • Quantitative analysis of Shh, Gli2, and Gli3 mRNA levels.
  • Phenotype rescue experiments using Smoothened agonist (SAG).

Main Results:

  • Dyrk1B overexpression decreased ventral progenitor, motor neuron (MN), and V2a interneuron numbers.
  • Pharmacological inhibition of Dyrk1B increased ventral progenitor and MN numbers.
  • Dyrk1B suppressed Shh, Gli2, and Gli3 mRNA levels; inhibition of Dyrk1B increased these transcript levels.
  • SAG rescued Dyrk1B-mediated dysregulation of ventral progenitors.
  • Dyrk1B selectively affected the medial lateral motor neuron column (LMCm) at E6.

Conclusions:

  • Dyrk1B kinase plays a novel regulatory role in suppressing the Shh/Gli pathway during embryonic spinal cord development.
  • Dyrk1B influences the proliferation, differentiation, and survival of ventral progenitor and motor neuron subtypes.
  • Dyrk1B emerges as a potential therapeutic target for motor neuron diseases.
Keywords:
ApoptosisChick neural tubeDyrk1BMotor neuronsNeuronal subtypesVentral progenitor domains

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