Presenilin gene function and Notch signaling feedback regulation in the developing mouse lens

Autor: Mina Azimi, Nadean L. Brown, Tien T. Le
Rok vydání: 2018
Předmět:
0301 basic medicine
Cancer Research
Gamma secretase
Cell
Mutant
Transgenic
Cell membrane
Lens
Mice
Receptors
2.1 Biological and endogenous factors
Receptor
Notch2
Aetiology
Notch signaling
Receptors
Notch
Cell Cycle
Presenilins
Lens development
Transmembrane protein
Cell biology
medicine.anatomical_structure
Signal Transduction
Receptor
Cell type
Notch
1.1 Normal biological development and functioning
Notch signaling pathway
Mice
Transgenic
Biology
Article
Presenilin
Paediatrics and Reproductive Medicine
03 medical and health sciences
Underpinning research
Lens
Crystalline
Genetics
medicine
Animals
Eye Disease and Disorders of Vision
Molecular Biology
Notch2
Crystalline
RBPJ
Cell Membrane
Cell Biology
Stem Cell Research
Psen
030104 developmental biology
Jagged1
Generic health relevance
Biochemistry and Cell Biology
Fiber cell differentiation
Developmental Biology
Zdroj: Differentiation. 102:40-52
ISSN: 0301-4681
DOI: 10.1016/j.diff.2018.07.003
Popis: Presenilins (Psen1 and Psen2 in mice) are polytopic transmembrane proteins that act in the γ-secretase complex to make intra-membrane cleavages of their substrates, including the well-studied Notch receptors. Such processing releases the Notch intracellular domain, allowing it to physically relocate from the cell membrane to the nucleus where it acts in a transcriptional activating complex to regulate downstream genes in the signal-receiving cell. Previous studies of Notch pathway mutants for Jagged1, Notch2, and Rbpj demonstrated that canonical signaling is a necessary component of normal mouse lens development. However, the central role of Psens within the γ-secretase complex has never been explored in any developing eye tissue or cell type. By directly comparing Psen single and double mutant phenotypes during mouse lens development, we found a stronger requirement for Psen1, although both genes are needed for progenitor cell growth and to prevent apoptosis. We also uncovered a novel genetic interaction between Psen1 and Jagged1. By quantifying protein and mRNA levels of key Notch pathway genes in Psen1/2 or Jagged1 mutant lenses, we identified multiple points in the overall signaling cascade where feedback regulation can occur. Our data are consistent with the loss of particular genes indirectly influencing the transcription level of another. However, we conclude that regulating Notch2 protein levels is particularly important during normal signaling, supporting the importance of post-translational regulatory mechanisms in this tissue.
Databáze: OpenAIRE
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