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Abstract: SA-PO332

Vessel-Promoting Factors npas4l/cloche and hand2 Act in Parallel to Inhibit Intermediate Mesoderm Specification

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 600 Development, Stem Cells, and Regenerative Medicine

Authors

  • Perens, Elliot, University of California San Diego, La Jolla, California, United States
  • Yelon, Deborah, University of California San Diego, La Jolla, California, United States
Background

Proper organ formation depends on precise organ territories containing defined numbers of progenitor cells. Kidney progenitors reside in the intermediate mesoderm (IM), two bilateral stripes of cells in the posterior mesoderm. Previously we showed that the transcription factors Hand2 and Osr1 are essential for defining the dimensions of the IM by balancing the specification of IM and laterally adjacent vessel progenitors. Recently the transcription factor Npas4l/Cloche – well characterized as an early, essential regulator of vessel and blood progenitor formation – was shown to inhibit kidney development. Here we determine how kidney and IM specification is coordinated among hand2, osr1, and npas4l.

Methods

Taking advantage of the robust genetic, optical, and experimental benefits of the zebrafish model organism, we interrogate the IM at the single cell level. Here we employ a combination of loss and gain-of-function genetic analyses and whole mount RNA in situ and antibody staining.

Results

First, hand2 and osr1 regulate the development of npas4l-expressing lateral vessel progenitors (LVPs). Interestingly, like hand2 loss-of-function, npas4l loss-of-function rescues osr1 mutant kidney developmental defects. However, unlike in hand2; osr1 double mutants in which LVP specification is restored, vessel progenitor formation is not rescued in npas4l; osr1 mutants, suggesting that hand2 and npas4l may implement different mechanisms to regulate kidney and vessel progenitor fates. Additionally, npas4l and hand2 overexpression can inhibit kidney formation independent of one another's function suggesting the two factors can function in parallel to inhibit kidney specification. Importantly, like hand2 mutants, npas4l mutants have expanded IM, but in npas4l mutants the increased IM is found outside hand2-expressing cells suggesting alternative sources of increased IM within the two mutants. Finally, consistent with parallel functions for hand2 and npas4l in IM inhibition, hand2; npas4l double mutants have increased IM beyond that seen in either single mutant.

Conclusion

Together our findings reveal that proper kidney specification depends on parallel genetic pathways that inhibit IM specification while promoting vessel progenitor formation

Funding

  • NIDDK Support