A non-canonical function of telomerase RNA in the regulation of developmental myelopoiesis in zebrafish.
Dyskeratosis congenita (DC) is an inherited disorder with mutations affecting telomerase or telomeric proteins. DC patients usually die of bone marrow failure. Here we show that genetic depletion of the telomerase RNA component (TR) in the zebrafish results in impaired myelopoiesis, despite normal development of haematopoietic stem cells (HSCs). The neutropenia caused by TR depletion is independent of telomere length and telomerase activity. Genetic analysis shows that TR modulates the myeloid-erythroid fate decision by controlling the levels of the master myeloid and erythroid transcription factors spi1 and gata1, respectively. The alteration in spi1 and gata1 levels occurs through stimulation of gcsf and mcsf. Our model of TR deficiency in the zebrafish illuminates the non-canonical roles of TR, and could establish therapeutic targets for DC.
1] Telomerase, Aging and Cancer Group, Research Unit, Department of Surgery, CIBERehd, University Hospital 'Virgen de la Arrixaca', 30120 Murcia, Spain [2] Instituto Murciano de Investigación Biosanitaria (IMIB), 30120 Murcia, Spain.
Francisca
F
Alcaraz-Pérez
1] Telomerase, Aging and Cancer Group, Research Unit, Department of Surgery, CIBERehd, University Hospital 'Virgen de la Arrixaca', 30120 Murcia, Spain [2] Instituto Murciano de Investigación Biosanitaria (IMIB), 30120 Murcia, Spain [3].
Jesús
J
García-Castillo
1] Telomerase, Aging and Cancer Group, Research Unit, Department of Surgery, CIBERehd, University Hospital 'Virgen de la Arrixaca', 30120 Murcia, Spain [2] Instituto Murciano de Investigación Biosanitaria (IMIB), 30120 Murcia, Spain [3] Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, 30100 Murcia, Spain [4].
Diana
D
García-Moreno
1] Instituto Murciano de Investigación Biosanitaria (IMIB), 30120 Murcia, Spain [2] Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, 30100 Murcia, Spain.
Azucena
A
López-Muñoz
1] Telomerase, Aging and Cancer Group, Research Unit, Department of Surgery, CIBERehd, University Hospital 'Virgen de la Arrixaca', 30120 Murcia, Spain [2] Instituto Murciano de Investigación Biosanitaria (IMIB), 30120 Murcia, Spain.
Monique
M
Anchelin
1] Instituto Murciano de Investigación Biosanitaria (IMIB), 30120 Murcia, Spain [2] Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, 30100 Murcia, Spain.
Diego
D
Angosto
1] Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA [2] Stem Cell Program, Children's Hospital Boston, Boston, Massachusetts 02115, USA [3] Division of Hematology/Oncology, Children's Hospital Boston, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Leonard I
LI
Zon
1] Instituto Murciano de Investigación Biosanitaria (IMIB), 30120 Murcia, Spain [2] Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, 30100 Murcia, Spain.
Victoriano
V
Mulero
1] Telomerase, Aging and Cancer Group, Research Unit, Department of Surgery, CIBERehd, University Hospital 'Virgen de la Arrixaca', 30120 Murcia, Spain [2] Instituto Murciano de Investigación Biosanitaria (IMIB), 30120 Murcia, Spain.
María L
ML
Cayuela
D000818:Animals; D001773:Blood Cells / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000201:enzymology*; D050982:GATA1 Transcription Factor / Q000378:metabolism; D006412:Hematopoietic Stem Cells; D038042:Myelopoiesis; D009503:Neutropenia; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012313:RNA / Q000378:metabolism*; D019098:Telomerase / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1
D050982:GATA1 Transcription Factor; D011518:Proto-Oncogene Proteins; D012313:RNA; D019098:Telomerase; D015534:Trans-Activators; D029961:Zebrafish Proteins; D000099232:Proto-Oncogene Protein Spi-1; C494691:gata1a protein, zebrafish; C422952:telomerase RNA