Mad dephosphorylation at the nuclear pore is essential for asymmetric stem cell division

Proc Natl Acad Sci U S A. 2021 Mar 30;118(13):e2006786118. doi: 10.1073/pnas.2006786118.


Stem cells divide asymmetrically to generate a stem cell and a differentiating daughter cell. Yet, it remains poorly understood how a stem cell and a differentiating daughter cell can receive distinct levels of niche signal and thus acquire different cell fates (self-renewal versus differentiation), despite being adjacent to each other and thus seemingly exposed to similar levels of niche signaling. In the Drosophila ovary, germline stem cells (GSCs) are maintained by short range bone morphogenetic protein (BMP) signaling; the BMP ligands activate a receptor that phosphorylates the downstream molecule mothers against decapentaplegic (Mad). Phosphorylated Mad (pMad) accumulates in the GSC nucleus and activates the stem cell transcription program. Here, we demonstrate that pMad is highly concentrated in the nucleus of the GSC, while it quickly decreases in the nucleus of the differentiating daughter cell, the precystoblast (preCB), before the completion of cytokinesis. We show that a known Mad phosphatase, Dullard (Dd), is required for the asymmetric partitioning of pMad. Our mathematical modeling recapitulates the high sensitivity of the ratio of pMad levels to the Mad phosphatase activity and explains how the asymmetry arises in a shared cytoplasm. Together, these studies reveal a mechanism for breaking the symmetry of daughter cells during asymmetric stem cell division.

Keywords: BMP signaling; Drosophila; Virtual Cell; asymmetric division; germline stem cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Asymmetric Cell Division / genetics*
  • Cell Nucleus
  • DNA-Binding Proteins / metabolism*
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster
  • Female
  • Nuclear Pore / metabolism*
  • Oocytes
  • Phosphoprotein Phosphatases / metabolism*
  • Phosphorylation / genetics
  • Stem Cells / physiology*
  • Transcription Factors / metabolism*
  • Transcriptional Activation


  • DNA-Binding Proteins
  • Drosophila Proteins
  • MAD protein, Drosophila
  • Transcription Factors
  • Dd protein, Drosophila
  • Phosphoprotein Phosphatases