Coupling organelle inheritance with mitosis to balance growth and differentiation
Amma Asare1, John Levorse1, Elaine Fuchs2
1Howard Hughes Medical Institute, Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY 10065, USA.
Abstract:
Balancing growth and differentiation is essential to tissue morphogenesis and homeostasis. How imbalances arise in disease states is poorly understood. To address this issue, we identified transcripts differentially expressed in mouse basal epidermal progenitors versus their differentiating progeny and those altered in cancers. We used an in vivo RNA interference screen to unveil candidates that altered the equilibrium between the basal proliferative layer and suprabasal differentiating layers forming the skin barrier. We found that epidermal progenitors deficient in the peroxisome-associated protein Pex11b failed to segregate peroxisomes properly and entered a mitotic delay that perturbed polarized divisions and skewed daughter fates. Together, our findings unveil a role for organelle inheritance in mitosis, spindle alignment, and the choice of daughter progenitors to differentiate or remain stem-like.
Insights
Proper organelle inheritance is crucial for cell division and tissue growth. Pex11b deficiency in epidermal progenitors disrupts peroxisome segregation, impacting cell division and stem cell fate.
Area of Science:
- Cell Biology
- Developmental Biology
- Cancer Research
Background:
- Tissue morphogenesis and homeostasis rely on balancing cell growth and differentiation.
- Understanding imbalances in these processes during disease is crucial but limited.
- Epidermal progenitors and their progeny exhibit distinct transcriptomic profiles, with alterations observed in cancer.
Purpose of the Study:
- To identify key factors regulating the balance between epidermal progenitor proliferation and differentiation.
- To investigate the mechanisms underlying imbalances in epidermal homeostasis.
- To uncover novel therapeutic targets for skin barrier disorders and cancers.
Main Methods:
- Differential gene expression analysis between mouse basal epidermal progenitors and differentiating progeny.
- In vivo RNA interference (RNAi) screen to identify genes affecting epidermal progenitor fate.
- Analysis of peroxisome segregation and mitotic spindle organization in Pex11b-deficient cells.
Main Results:
- Identification of differentially expressed transcripts in epidermal progenitors and cancer-related alterations.
- An in vivo RNAi screen revealed candidates impacting the proliferation-differentiation equilibrium.
- Epidermal progenitors lacking Pex11b showed impaired peroxisome segregation, leading to mitotic delay.
- Deficiency in Pex11b perturbed polarized cell divisions and skewed daughter cell fates.
Conclusions:
- Organelle inheritance plays a significant role in regulating cell division and spindle alignment.
- Pex11b is critical for proper peroxisome segregation during mitosis.
- Disrupted organelle inheritance can lead to altered cell fates, impacting tissue homeostasis and potentially contributing to disease.
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