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The UFM1 cascade times mitosis entry associated with microcephaly

Li Yu1,2, Guangxu Li1,2, Jing Deng1,2

  • 1Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|January 10, 2020
PubMed

Insights

The UFM1 cascade is crucial for brain development, as its disruption causes microcephaly by impairing cell division and mitotic progression in neuroblasts.

Area of Science:

  • Cell Biology
  • Developmental Biology
  • Genetics

Background:

  • Posttranslational modifications, like ufmylation, diversify proteome function.
  • The UFM1 cascade, a ubiquitin-like modification system, is implicated in microcephaly.
  • Pathological mechanisms linking UFM1 mutations to microcephaly are not fully understood.

Purpose of the Study:

  • To investigate the role of the UFM1 cascade in neurodevelopment and cell cycle regulation.
  • To elucidate the pathological mechanisms underlying UFM1-associated microcephaly.

Main Methods:

  • Disruption of the UFM1 cascade in Drosophila neuroblasts and embryos.
  • Live imaging of embryonic development.
  • Analysis of mitotic progression, centrosome, microtubule, and DNA integrity.
  • Assessment of CDK1 phosphorylation levels.

Main Results:

  • Disruption of the UFM1 cascade in Drosophila neuroblasts reduced neuroblast numbers and brain size.
  • Lack of ufmylation led to increased mitotic index and extended G2/M phase, indicating defective mitotic progression.
  • Impaired Ufl1 function caused premature mitotic entry, failed cellularization, and embryonic lethality.
  • Observed phenotypes included detached centrosomes, defective microtubules, and DNA bridges.
  • The UFM1 cascade regulates CDK1 phosphorylation at tyrosine-15, a key cell cycle regulator.

Conclusions:

  • The UFM1 cascade is essential for proper neuroblast proliferation and mitotic progression.
  • Defects in the UFM1 cascade contribute to microcephaly by disrupting cell cycle control.
  • UFM1 cascade dysfunction impacts key mitotic events, including centrosome stability and microtubule dynamics.
Keywords:
Drosophilacell cyclemicrocephalyufmylation

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