Paths and pathways that generate cell-type heterogeneity and developmental progression in hematopoiesis

Author:

Girard Juliet R1ORCID,Goins Lauren M1,Vuu Dung M1,Sharpley Mark S1,Spratford Carrie M1,Mantri Shreya R1,Banerjee Utpal1234ORCID

Affiliation:

1. Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles

2. Molecular Biology Institute, University of California, Los Angeles

3. Department of Biological Chemistry, University of California, Los Angeles

4. Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles

Abstract

Mechanistic studies of Drosophila lymph gland hematopoiesis are limited by the availability of cell-type-specific markers. Using a combination of bulk RNA-Seq of FACS-sorted cells, single-cell RNA-Seq, and genetic dissection, we identify new blood cell subpopulations along a developmental trajectory with multiple paths to mature cell types. This provides functional insights into key developmental processes and signaling pathways. We highlight metabolism as a driver of development, show that graded Pointed expression allows distinct roles in successive developmental steps, and that mature crystal cells specifically express an alternate isoform of Hypoxia-inducible factor (Hif/Sima). Mechanistically, the Musashi-regulated protein Numb facilitates Sima-dependent non-canonical, and inhibits canonical, Notch signaling. Broadly, we find that prior to making a fate choice, a progenitor selects between alternative, biologically relevant, transitory states allowing smooth transitions reflective of combinatorial expressions rather than stepwise binary decisions. Increasingly, this view is gaining support in mammalian hematopoiesis.

Funder

National Heart, Lung, and Blood Institute

National Cancer Institute

National Institute of General Medical Sciences

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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