Abstract
The transition of hematopoiesis from the fetal liver (FL) to the bone marrow (BM) is incompletely characterized. We demonstrate that the Wiskott–Aldrich syndrome verprolin-homologous protein (WAVE) complex 2 is required for this transition, as complex degradation via deletion of its scaffold Hem-1 causes the premature exhaustion of neonatal BM hematopoietic stem cells (HSCs). This exhaustion of BM HSC is due to the failure of BM engraftment of Hem-1−/− FL HSCs, causing early death. The Hem-1−/− FL HSC engraftment defect is not due to the lack of the canonical function of the WAVE2 complex, the regulation of actin polymerization, because FL HSCs from Hem-1−/− mice exhibit no defects in chemotaxis, BM homing, or adhesion. Rather, the failure of Hem-1−/− FL HSC engraftment in the marrow is due to the loss of c-Abl survival signaling from degradation of the WAVE2 complex. However, c-Abl activity is dispensable for the engraftment of adult BM HSCs into the BM. These findings reveal a novel function of the WAVE2 complex and define a mechanism for FL HSC fitness in the embryonic BM niche.
Highlights
The transition of hematopoiesis from the fetal liver (FL) to the bone marrow (BM) is incompletely characterized
We hypothesized that the hematopoietic-specific Wiskott–Aldrich syndrome verprolinhomologous protein (WAVE) complex scaffold Hem-1 is important for FL hematopoietic stem cells (HSCs) transition to the BM
Hem-1−/− mice exhibited growth retardation and died prematurely after birth, with an average life expectancy of 6 weeks (Fig. 1b, c). These abnormalities were associated with a dramatic defect in BM hematopoiesis, including a significant reduction in the number of total BM nucleated cells (BMCs), BM phenotypic HSCs and hematopoietic progenitor cells (HPCs), and BM cobblestone area-forming cells (CAFCs) in 5-week-old Hem-1−/− compared with littermate Hem-1+/+ mice of the same age (Fig. 1d–h)
Summary
The transition of hematopoiesis from the fetal liver (FL) to the bone marrow (BM) is incompletely characterized. We demonstrate that the Wiskott–Aldrich syndrome verprolinhomologous protein (WAVE) complex 2 is required for this transition, as complex degradation via deletion of its scaffold Hem-1 causes the premature exhaustion of neonatal BM hematopoietic stem cells (HSCs). This exhaustion of BM HSC is due to the failure of BM engraftment of Hem-1−/− FL HSCs, causing early death. Hematopoietic stem cells (HSCs) migrate from their sites of origin to the fetal liver (FL) on embryonic day (E) 9.5–10.5 in murine development[1,2,3] This transient residence in the FL is essential for the maturation of adult HSCs and functional adult hematopoiesis[3,4,5]. This defines a novel WAVE complex function, survival signaling, and sheds light on the regulation of the transition of hematopoiesis from the FL to the marrow during development
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