CaM kinase IV regulates lineage commitment and survival of erythroid progenitors in a non-cell-autonomous manner.
Developmental functions of calmodulin-dependent protein kinase IV (CaM KIV) have not been previously investigated. Here, we show that CaM KIV transcripts are widely distributed during embryogenesis and that strict regulation of CaM KIV activity is essential for normal primitive erythropoiesis. Xenopus embryos in which CaM KIV activity is either upregulated or inhibited show that hematopoietic precursors are properly specified, but few mature erythrocytes are generated. Distinct cellular defects underlie this loss of erythrocytes: inhibition of CaM KIV activity causes commitment of hematopoietic precursors to myeloid differentiation at the expense of erythroid differentiation, on the other hand, constitutive activation of CaM KIV induces erythroid precursors to undergo apoptotic cell death. These blood defects are observed even when CaM KIV activity is misregulated only in cells that do not contribute to the erythroid lineage. Thus, proper regulation of CaM KIV activity in nonhematopoietic tissues is essential for the generation of extrinsic signals that enable hematopoietic stem cell commitment to erythroid differentiation and that support the survival of erythroid precursors.
Wayman
G A
GA
Vollum Institute, Oregon Health Sciences University, Portland, Oregon 97201-3098, USA.
Walters
M J
MJ
Kolibaba
K
K
Soderling
T R
TR
Christian
J L
JL
D000595:Amino Acid Sequence; D000818:Animals; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D002470:Cell Survival / Q000502:physiology; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000502:physiology*; D004912:Erythrocytes / Q000166:cytology; D015672:Erythroid Precursor Cells / Q000166:cytology* / Q000502:physiology; D004920:Erythropoiesis; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D051379:Mice; D008969:Molecular Sequence Data; D009024:Morphogenesis; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D011994:Recombinant Proteins / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014158:Transcription, Genetic; D014982:Xenopus laevis
D011994:Recombinant Proteins; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517685:Camk4 protein, mouse