title: Atypical protein kinase C (aPKCzeta and aPKClambda) is dispensable for mammalian hematopoietic stem cell activity and blood formation.
abstract: The stem-cell pool is considered to be maintained by a balance between symmetric and asymmetric division of stem cells. The cell polarity model proposes that the facultative use of symmetric and asymmetric cell division is orchestrated by a polarity complex consisting of partitioning-defective proteins Par3 and Par6, and atypical protein kinase C (aPKCζ and aPKCλ), which regulates planar symmetry of dividing stem cells with respect to the signaling microenvironment. However, the role of the polarity complex is unexplored in mammalian adult stem-cell functions. Here we report that, in contrast to accepted paradigms, polarization and activity of adult hematopoietic stem cell (HSC) do not depend on either aPKCζ or aPKCλ or both in vivo. Mice, having constitutive and hematopoietic-specific (Vav1-Cre) deletion of aPKCζ and aPKCλ, respectively, have normal hematopoiesis, including normal HSC self-renewal, engraftment, differentiation, and interaction with the bone marrow microenvironment. Furthermore, inducible complete deletion of aPKCλ (Mx1-Cre) in aPKCζ(-/-) HSC does not affect HSC polarization, self-renewal, engraftment, or lineage repopulation. In addition, aPKCζ- and aPKCλ-deficient HSCs elicited a normal pattern of hematopoietic recovery secondary to myeloablative stress. Taken together, the expression of aPKCζ, aPKCλ, or both are dispensable for primitive and adult HSC fate determination in steady-state and stress hematopoiesis, contrary to the hypothesis of a unique, evolutionary conserved aPKCζ/λ-directed cell polarity signaling mechanism in mammalian HSC fate determination.
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Amitava
authors.initials: A
authors.lastname: Sengupta
authors.forename: Angeles
authors.initials: A
authors.lastname: Duran
authors.forename: Eri
authors.initials: E
authors.lastname: Ishikawa
authors.forename: Maria Carolina
authors.initials: MC
authors.lastname: Florian
authors.forename: Susan K
authors.initials: SK
authors.lastname: Dunn
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Ficker
authors.forename: Michael
authors.initials: M
authors.lastname: Leitges
authors.forename: Hartmut
authors.initials: H
authors.lastname: Geiger
authors.forename: Maria
authors.initials: M
authors.lastname: Diaz-Meco
authors.forename: Jorge
authors.initials: J
authors.lastname: Moscat
authors.forename: Jose A
authors.initials: JA
authors.lastname: Cancelas
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D016764:Cell Polarity; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011493:Protein Kinase C / Q000172:deficiency* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000099293:Protein Kinase C-lambda; D000099221:Protein Kinase C zeta
chemical_list: D007527:Isoenzymes; D011493:Protein Kinase C; D000099293:Protein Kinase C-lambda; D000099221:Protein Kinase C zeta; C115015:PKC-3 protein