A defect in hematopoietic stem cell migration explains the nonrandom X-chromosome inactivation in carriers of Wiskott-Aldrich syndrome.
A defect in cell trafficking and chemotaxis plays an important role in the immune deficiency observed in Wiskott-Aldrich syndrome (WAS). In this report, we show that marrow cells from WAS protein (WASP)-deficient mice also have a defect in chemotaxis. Serial transplantation and competitive reconstitution experiments demonstrated that marrow cells, including hematopoietic progenitors and stem cells (HSCs), have decreased homing capacities that were associated with a defect in adhesion to collagen. During development, HSCs migrate from the liver to the marrow and the spleen, prompting us to ask if a defect in HSC homing during development may explain the skewed X-chromosome inactivation in WAS carriers. Preliminary evidence has shown that, in contrast to marrow progenitor cells, fetal liver progenitor cells from heterozygous females had a random X-chromosome inactivation. When fetal liver cells from WASP-carrier females were injected into irradiated recipients, a nonrandom inactivation of the X-chromosome was found at the level of hematopoietic progenitors and HSCs responsible for the short- and long-term hematopoietic reconstitution. Therefore, the mechanism of the skewed X-chromosomal inactivation observed in WAS carriers may be related to a migration defect of WASP-deficient HSCs.
Lacout
Catherine
C
U362 Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy, Villejuif, France.
Haddad
Elie
E
Sabri
Siham
S
Svinarchouk
Fedor
F
Garçon
Loic
L
Capron
Claude
C
Foudi
Adlen
A
Mzali
Rym
R
Snapper
Scott B
SB
Louache
Fawzia
F
Vainchenker
William
W
Duménil
Dominique
D
D000199:Actins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology; D002633:Chemotaxis / Q000502:physiology*; D003094:Collagen / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D004303:Dosage Compensation, Genetic; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D005982:Glutathione Transferase / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology*; D006579:Heterozygote; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D051316:Wiskott-Aldrich Syndrome Protein; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
D000199:Actins; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D011506:Proteins; C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein; D003094:Collagen; D005982:Glutathione Transferase; D020764:cdc42 GTP-Binding Protein; D005472:Fluorouracil