Wnt9a Is Required for the Aortic Amplification of Nascent Hematopoietic Stem Cells

Stephanie Grainger; Jenna Richter; Raquel Espín Palazón; Claire Pouget; Brianna Lonquich; Sara Wirth; Kathrin Sabine Grassme; Wiebke Herzog; Matthew R Swift; Brant M Weinstein; David Traver; Karl Willert

doi:10.1016/j.celrep.2016.10.027

Wnt9a Is Required for the Aortic Amplification of Nascent Hematopoietic Stem Cells

Cell Rep. 2016 Nov 1;17(6):1595-1606. doi: 10.1016/j.celrep.2016.10.027.

Affiliations

¹ Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
² Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92037, USA; Biomedical Sciences Graduate Studies, University of California, San Diego, La Jolla, CA 92037, USA.
³ University of Münster, 48149 Münster, Germany.
⁴ University of Münster, 48149 Münster, Germany; Max-Planck-Institute for Molecular Biomedicine, Münster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), University of Münster, 48149 Münster, Germany.
⁵ Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA.
⁶ Section on Vertebrate Organogenesis, Division of Developmental Biology, NICHD, NIH, Bethesda, MD 20892, USA.
⁷ Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92037, USA. Electronic address: dtraver@ucsd.edu.
⁸ Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92037, USA. Electronic address: kwillert@ucsd.edu.

Abstract

All mature blood cell types in the adult animal arise from hematopoietic stem and progenitor cells (HSPCs). However, the developmental cues regulating HSPC ontogeny are incompletely understood. In particular, the details surrounding a requirement for Wnt/β-catenin signaling in the development of mature HSPCs are controversial and difficult to consolidate. Using zebrafish, we demonstrate that Wnt signaling is required to direct an amplification of HSPCs in the aorta. Wnt9a is specifically required for this process and cannot be replaced by Wnt9b or Wnt3a. This proliferative event occurs independently of initial HSPC fate specification, and the Wnt9a input is required prior to aorta formation. HSPC arterial amplification occurs prior to seeding of secondary hematopoietic tissues and proceeds, in part, through the cell cycle regulator myca (c-myc). Our results support a general paradigm, in which early signaling events, including Wnt, direct later HSPC developmental processes.

Keywords: HSCs; HSPCs; Myc; Wnt; Wnt9a; aorta; hematopoietic stem and progenitor cells; hematopoietic stem cells; proliferation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Aorta / cytology*
Aorta / embryology*
Cell Count
Cell Cycle
Cell Proliferation
Hemangioblasts / metabolism
Hematopoietic Stem Cells / cytology*
Hematopoietic Stem Cells / metabolism*
Wnt Proteins / metabolism*
Wnt Signaling Pathway
Zebrafish / embryology*
Zebrafish Proteins / metabolism*

Substances

Wnt Proteins
Wnt9a protein, zebrafish
Zebrafish Proteins

Grants and funding

R01 HL135205/HL/NHLBI NIH HHS/United States