title: Asymmetric segregation and self-renewal of hematopoietic stem and progenitor cells with endocytic Ap2a2.
abstract: The stem cell-intrinsic model of self-renewal via asymmetric cell division (ACD) posits that fate determinants be partitioned unequally between daughter cells to either activate or suppress the stemness state. ACD is a purported mechanism by which hematopoietic stem cells (HSCs) self-renew, but definitive evidence for this cellular process remains open to conjecture. To address this issue, we chose 73 candidate genes that function within the cell polarity network to identify potential determinants that may concomitantly alter HSC fate while also exhibiting asymmetric segregation at cell division. Initial gene-expression profiles of polarity candidates showed high and differential expression in both HSCs and leukemia stem cells. Altered HSC fate was assessed by our established in vitro to in vivo screen on a subcohort of candidate polarity genes, which revealed 6 novel positive regulators of HSC function: Ap2a2, Gpsm2, Tmod1, Kif3a, Racgap1, and Ccnb1. Interestingly, live-cell videomicroscopy of the endocytic protein AP2A2 shows instances of asymmetric segregation during HSC/progenitor cell cytokinesis. These results contribute further evidence that ACD is functional in HSC self-renewal, suggest a role for Ap2a2 in HSC activity, and provide a unique opportunity to prospectively analyze progeny from HSC asymmetric divisions.
authors.affiliation: Molecular Genetics of Stem Cells Laboratory, Institute of Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC, Canada. stephen.ting@monash.edu
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Ting
authors.forename: Eric
authors.initials: E
authors.lastname: Deneault
authors.forename: Kristin
authors.initials: K
authors.lastname: Hope
authors.forename: Sonia
authors.initials: S
authors.lastname: Cellot
authors.forename: Jalila
authors.initials: J
authors.lastname: Chagraoui
authors.forename: Nadine
authors.initials: N
authors.lastname: Mayotte
authors.forename: Jonas F
authors.initials: JF
authors.lastname: Dorn
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Laverdure
authors.forename: Michael
authors.initials: M
authors.lastname: Harvey
authors.forename: Edwin D
authors.initials: ED
authors.lastname: Hawkins
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Russell
authors.forename: Paul S
authors.initials: PS
authors.lastname: Maddox
authors.forename: Norman N
authors.initials: NN
authors.lastname: Iscove
authors.forename: Guy
authors.initials: G
authors.lastname: Sauvageau
mesh_terms: D033962:Adaptor Protein Complex 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D033965:Adaptor Protein Complex alpha Subunits / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D060049:Asymmetric Cell Division / Q000502:physiology*; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002454:Cell Differentiation; D019070:Cell Lineage; D016764:Cell Polarity / Q000235:genetics*; D049109:Cell Proliferation; D004705:Endocytosis / Q000235:genetics*; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology; D007938:Leukemia / Q000378:metabolism / Q000473:pathology; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology* / Q000502:physiology
chemical_list: D033962:Adaptor Protein Complex 2; D033965:Adaptor Protein Complex alpha Subunits; D015415:Biomarkers; D012333:RNA, Messenger; C439124:adaptor protein complex 2, alpha 2 subunit