Cell Adhesion Geometry Regulates Non-Random DNA Segregation and Asymmetric Cell Fates in Mouse Skeletal Muscle Stem Cells

• Extrinsic adhesion cues regulate non-random DNA segregation and cell fates
• Old DNA strands segregate with muscle stem cells on micropatterns
• Daughter cells retaining old DNA strands preferentially localize to areas of low adhesion
• Transcription factor asymmetry and biased DNA segregation can be uncoupled

SummaryCells of several metazoan species have been shown to non-randomly segregate their DNA such that older template DNA strands segregate to one daughter cell. The mechanisms that regulate this asymmetry remain undefined. Determinants of cell fate are polarized during mitosis and partitioned asymmetrically as the spindle pole orients during cell division. Chromatids align along the pole axis; therefore, it is unclear whether extrinsic cues that determine spindle pole position also promote non-random DNA segregation. To mimic the asymmetric divisions seen in the mouse skeletal stem cell niche, we used micropatterns coated with extracellular matrix in asymmetric and symmetric motifs. We show that the frequency of non-random DNA segregation and transcription factor asymmetry correlates with the shape of the motif and that these events can be uncoupled. Furthermore, regulation of DNA segregation by cell adhesion occurs within a defined time interval. Thus, cell adhesion cues have a major impact on determining both DNA segregation patterns and cell fates.

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