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Abstract: TH-PO390

Regulators of Intermediate Mesoderm Development Impact Neighboring Vessel Progenitor 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
  • Stouthart, Elizabeth Willemijn, University of California San Diego, La Jolla, California, United States
  • Nunes, Matthew, University of California San Diego, La Jolla, California, United States
  • Yelon, Deborah, University of California San Diego, La Jolla, California, United States
Background

Congenital anomalies of the kidney and urinary tract (CAKUT) are diagnosed in 1 out of 500 live births, and pathogenic mutations have been identified more than 50 genes. Many of these genes, including the two most frequently mutated genes, PAX2 and HNF1β, have been implicated in early aspects of kidney development. The first step in kidney development is the specification of kidney progenitors within the intermediate mesoderm (IM), a pair of bilateral territories within the posterior mesoderm, flanked by tissues that give rise to vessels, blood, muscle, bone, and peritoneum.

Our previous work in the zebrafish model system highlighted a coupling of IM formation with the development of neighboring vessel progenitors (VPs). We demonstrated that the transcription factors Hand2 and Osr1 act in opposition at the lateral border of the IM to balance the specification of IM and VPs (Perens et al., 2016; Perens et al., 2021). More recently we found that the transcription factor Npas4l (Cloche), an early essential regulator of VP formation, is required to inhibit IM formation at both the lateral and medial IM borders (Perens and Yelon, 2024).

Methods

Genetic analyses, molecular anatomical studies, single cell RNA-seq, genetic lineage analysis

Results

First, surprisingly, our genetic analyses suggest that genes expressed in and necessary for IM development – pax2a and pax8 – are required for formation of VPs at the lateral IM border while inhibiting excessive VP formation at the medial border. Second, we observe that lateral VPs co-express genes associated with VP (ie. etv2) and IM fates (ie. pax2a). Third, our preliminary scRNA-seq data on IM cells (obtained by sorting cells double positive for pax2a and hnf1βa transgenes) further suggest that the IM is divided into subdomains with unique transcriptional signatures and divergent developmental potentials, including a domain capable of generating IM and VPs.

Conclusion

Together, our data further highlight intriguing genetic and lineage relationships between the IM and neighboring VPs.

Funding

  • NIDDK Support