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Jagged1 protein processing in the developing mammalian lens.

Mina Azimi1, Nadean L Brown2

  • 1Department of Cell Biology & Human Anatomy, University of California, 1 Shields Avenue, Davis, CA 95616, USA.

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|March 21, 2019
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Summary

Jagged1 protein undergoes processing by gamma-secretase, producing active intracellular domains in lens progenitor cells. This post-translational regulation impacts Notch signaling during vertebrate development.

Keywords:
ADAM proteaseGamma secretase (γ-secretase)Jagged1Lens developmentNotch signalingPresenilin

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Area of Science:

  • Developmental Biology
  • Cell Signaling
  • Molecular Biology

Background:

  • Notch signaling is crucial for ocular lens development, regulating progenitor cell growth and differentiation.
  • Receptor processing involves ADAM proteases and gamma-secretase, releasing the Notch intracellular domain (N-ICD) to activate target genes.
  • Previous in vitro studies suggested gamma-secretase cleavage of Notch ligands, but in vivo evidence was lacking.

Purpose of the Study:

  • To investigate the in vivo processing of Jagged1, a Notch ligand, during vertebrate ocular lens development.
  • To determine if Jagged1 intracellular domain is produced and functional in lens progenitor cells.
  • To explore the post-translational regulation of Jagged1 in vivo.

Main Methods:

  • Analysis of Jagged1 protein isoforms in mouse and human lens progenitor cells.
  • In vitro experiments using pharmacologic gamma-secretase inhibitors.
  • Overexpression studies of epitope-tagged Jagged1 intracellular domain.

Main Results:

  • Multiple Jagged1 protein isoforms, including an intracellular domain, are endogenously expressed in lens progenitor cells.
  • Gamma-secretase inhibition in vitro leads to accumulation of Jagged1 polypeptide intermediates.
  • Overexpressed Jagged1 intracellular domain localizes to the nucleus and upregulates JAG1 mRNA.

Conclusions:

  • Jagged1 is post-translationally regulated in vivo, generating multiple active protein isoforms.
  • The Jagged1 intracellular domain may play a role in regulating its own gene expression.
  • These findings expand the understanding of Jagged1 function beyond its role as a simple Notch ligand.