MELK is Required for G2/M Phase Progression in Cortical Progenitors: Insights from Rare ASD-Associated Variants

Liyang Zhao1, Xianjing Li1, Kang Yang1

  • 1National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), NHC Key Laboratory of Mental Health (Peking University), Peking University Sixth Hospital, Peking University Institute of Mental Health, No. 51 Huayuanbei Road, Haidian District, Beijing, 100191, China.

Insights

Maternal embryonic leucine zipper kinase (MELK) is crucial for embryonic brain development. This study reveals MELK regulates neural progenitor cell cycle and neuron formation, linking it to neurodevelopmental conditions like autism spectrum disorder (ASD).

Area of Science:

  • Neuroscience
  • Developmental Biology
  • Genetics

Background:

  • Maternal embryonic leucine zipper kinase (MELK) is a known cell cycle regulator.
  • Its specific function in embryonic cortical development and neurodevelopmental conditions like autism spectrum disorder (ASD) is largely unknown.

Purpose of the Study:

  • To investigate the role of MELK in embryonic cortical development.
  • To explore the potential mechanistic link between MELK function and neurodevelopmental conditions.

Main Methods:

  • Analysis of ultra-rare MELK variants in individuals with ASD.
  • In utero electroporation in mouse models to assess Melk knockdown effects.
  • Single-cell transcriptomics and FACS-sorted cell analysis to examine gene expression changes.

Main Results:

  • MELK expression is enriched in neural progenitors and correlates with the G2/M phase of the cell cycle.
  • Melk knockdown in mice impairs progenitor cell cycle progression (G2/M phase) and neuronal migration.
  • Downregulation of G2/M phase genes and cytoskeletal regulators involved in neuronal morphogenesis was observed in Melk-knockdown cells.

Conclusions:

  • MELK is identified as a critical regulator of G2/M phase progression in neural progenitors during cortical development.
  • MELK plays a vital role in neuronal morphogenesis, impacting cell migration and process extension.
  • These findings establish a mechanistic link between MELK dysfunction and neurodevelopmental conditions.

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