Defective Erythroid Maturation in Gelsolin Mutant Mice

Overview

Journal Haematologica

Specialty Hematology

Date 2012 Jan 25

PMID 22271892

Citations 7

Authors

Claudio Cantu

Francesca Bose

Paola Bianchi

Eva Reali

Maria Teresa Colzani

Ileana Cantu

Gloria Barbarani

Sergio Ottolenghi

Walter Witke

Laura Spinardi

Antonella Ellena Ronchi

Affiliations

Soon will be listed here.

Abstract

Background: During late differentiation, erythroid cells undergo profound changes involving actin filament remodeling. One of the proteins controlling actin dynamics is gelsolin, a calcium-activated actin filament severing and capping protein. Gelsolin-null (Gsn(-/-)) mice generated in a C57BL/6 background are viable and fertile.1

Design And Methods: We analyzed the functional roles of gelsolin in erythropoiesis by: (i) evaluating gelsolin expression in murine fetal liver cells at different stages of erythroid differentiation (using reverse transcription polymerase chain reaction analysis and immunohistochemistry), and (ii) characterizing embryonic and adult erythropoiesis in Gsn(-/-) BALB/c mice (morphology and erythroid cultures).

Results: In the context of a BALB/c background, the Gsn(-/-) mutation causes embryonic death. Gsn(-/-) embryos show defective erythroid maturation with persistence of circulating nucleated cells. The few Gsn(-/-) mice reaching adulthood fail to recover from phenylhydrazine-induced acute anemia, revealing an impaired response to stress erythropoiesis. In in vitro differentiation assays, E13.5 fetal liver Gsn(-/-) cells failed to undergo terminal maturation, a defect partially rescued by Cytochalasin D, and mimicked by administration of Jasplakinolide to the wild-type control samples.

Conclusions: In BALB/c mice, gelsolin deficiency alters the equilibrium between erythrocyte actin polymerization and depolymerization, causing impaired terminal maturation. We suggest a non-redundant role for gelsolin in terminal erythroid differentiation, possibly contributing to the Gsn(-/-) mice lethality observed in mid-gestation.

Citing Articles

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Erythroid enucleation: a gateway into a "bloody" world.

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Lees J, White D, Keating B, Barkl-Luke M, Makker P, Goldstein D PLoS One. 2020; 15(9):e0238164.

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Cellular dynamics of mammalian red blood cell production in the erythroblastic island niche.

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Uras I, Scheicher R, Kollmann K, Glosmann M, Prchal-Murphy M, Tigan A Haematologica. 2017; 102(6):995-1005.

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References

Queisser W, Spiertz E, Jost E, Heimpel H . Proliferation disturbances of erythroblasts in congenital dyserythropoietic anemia type I and II. Acta Haematol. 1971; 45(2):65-76. DOI: 10.1159/000208608. View

Koury S, Koury M, Bondurant M . Cytoskeletal distribution and function during the maturation and enucleation of mammalian erythroblasts. J Cell Biol. 1989; 109(6 Pt 1):3005-13. PMC: 2115945. DOI: 10.1083/jcb.109.6.3005. View

Chen H, Khan A, Liu F, Gilligan D, Peters L, Messick J . Combined deletion of mouse dematin-headpiece and beta-adducin exerts a novel effect on the spectrin-actin junctions leading to erythrocyte fragility and hemolytic anemia. J Biol Chem. 2006; 282(6):4124-35. DOI: 10.1074/jbc.M610231200. View

Chu X, Chen J, Reedy M, Vera C, Paul Sung K, Sung L . E-Tmod capping of actin filaments at the slow-growing end is required to establish mouse embryonic circulation. Am J Physiol Heart Circ Physiol. 2003; 284(5):H1827-38. DOI: 10.1152/ajpheart.00947.2002. View

Ney P . Normal and disordered reticulocyte maturation. Curr Opin Hematol. 2011; 18(3):152-7. PMC: 3157046. DOI: 10.1097/MOH.0b013e328345213e. View

Doetschman T . Influence of genetic background on genetically engineered mouse phenotypes. Methods Mol Biol. 2009; 530:423-33. PMC: 2805848. DOI: 10.1007/978-1-59745-471-1_23. View

Birkenmeier C, Barker J . Hereditary haemolytic anaemias: unexpected sequelae of mutations in the genes for erythroid membrane skeletal proteins. J Pathol. 2004; 204(4):450-9. DOI: 10.1002/path.1636. View

Chasis J, Mohandas N . Erythroblastic islands: niches for erythropoiesis. Blood. 2008; 112(3):470-8. PMC: 2481536. DOI: 10.1182/blood-2008-03-077883. View

Muro A, Marro M, Gajovic S, Porro F, Luzzatto L, Baralle F . Mild spherocytic hereditary elliptocytosis and altered levels of alpha- and gamma-adducins in beta-adducin-deficient mice. Blood. 2000; 95(12):3978-85. View

10.

Tanaka J, Kira M, Sobue K . Gelsolin is localized in neuronal growth cones. Brain Res Dev Brain Res. 1993; 76(2):268-71. DOI: 10.1016/0165-3806(93)90217-x. View

11.

Barkalow K, Witke W, Kwiatkowski D, Hartwig J . Coordinated regulation of platelet actin filament barbed ends by gelsolin and capping protein. J Cell Biol. 1996; 134(2):389-99. PMC: 2120875. DOI: 10.1083/jcb.134.2.389. View

12.

Delaunay J . The molecular basis of hereditary red cell membrane disorders. Blood Rev. 2006; 21(1):1-20. DOI: 10.1016/j.blre.2006.03.005. View

13.

Soni S, Bala S, Kumar A, Hanspal M . Changing pattern of the subcellular distribution of erythroblast macrophage protein (Emp) during macrophage differentiation. Blood Cells Mol Dis. 2006; 38(1):25-31. PMC: 1857287. DOI: 10.1016/j.bcmd.2006.09.005. View

14.

Kalfa T, Pushkaran S, Mohandas N, Hartwig J, Fowler V, Johnson J . Rac GTPases regulate the morphology and deformability of the erythrocyte cytoskeleton. Blood. 2006; 108(12):3637-45. PMC: 1895472. DOI: 10.1182/blood-2006-03-005942. View

15.

Liu X, Li X, Wang Y, Shu R, Wang L, Lu S . Disruption of palladin leads to defects in definitive erythropoiesis by interfering with erythroblastic island formation in mouse fetal liver. Blood. 2007; 110(3):870-6. DOI: 10.1182/blood-2007-01-068528. View

16.

Mohandas N, Gallagher P . Red cell membrane: past, present, and future. Blood. 2008; 112(10):3939-48. PMC: 2582001. DOI: 10.1182/blood-2008-07-161166. View

17.

Chen K, Liu J, Heck S, Chasis J, An X, Mohandas N . Resolving the distinct stages in erythroid differentiation based on dynamic changes in membrane protein expression during erythropoiesis. Proc Natl Acad Sci U S A. 2009; 106(41):17413-8. PMC: 2762680. DOI: 10.1073/pnas.0909296106. View

18.

Lueck A, Yin H, Kwiatkowski D, Allen P . Calcium regulation of gelsolin and adseverin: a natural test of the helix latch hypothesis. Biochemistry. 2000; 39(18):5274-9. DOI: 10.1021/bi992871v. View

19.

Gutierrez L, Lindeboom F, Ferreira R, Drissen R, Grosveld F, Whyatt D . A hanging drop culture method to study terminal erythroid differentiation. Exp Hematol. 2005; 33(10):1083-91. DOI: 10.1016/j.exphem.2005.06.014. View

20.

Gilligan D, Lozovatsky L, Gwynn B, Brugnara C, Mohandas N, Peters L . Targeted disruption of the beta adducin gene (Add2) causes red blood cell spherocytosis in mice. Proc Natl Acad Sci U S A. 1999; 96(19):10717-22. PMC: 17949. DOI: 10.1073/pnas.96.19.10717. View