Development of mice expressing a single D-type cyclin.
D-cyclins (cyclins D1, D2, and D3) are components of the core cell cycle machinery. To directly test the ability of each D-cyclin to drive development of various lineages, we generated mice expressing only cyclin D1, or only cyclin D2, or only cyclin D3. We found that these "single-cyclin" embryos develop normally until late gestation. Our analyses revealed that in single-cyclin embryos, the tissue-specific expression pattern of D-cyclins was lost. Instead, mutant embryos ubiquitously expressed the remaining D-cyclin. These findings suggest that the functions of the three D-cyclins are largely exchangeable at this stage. Later in life, single-cyclin mice displayed focused abnormalities, resulting in premature mortality. "Cyclin D1-only" mice developed severe megaloblastic anemia, "cyclin D2-only" mice presented neurological abnormalities, and "cyclin D3-only" mice lacked normal cerebella. Analyses of the affected tissues revealed that these compartments failed to sufficiently up-regulate the remaining, intact D-cyclin. In particular, we found that in cerebellar granule neuron precursors, the N-myc transcription factor communicates with the cell cycle machinery via cyclins D1 and D2, but not D3, explaining the inability of D3-only mice to up-regulate cyclin D3 in this compartment. Hence, the requirement for a particular cyclin in a given tissue is likely caused by specific transcription factors, rather than by unique properties of cyclins.
Ciemerych
Maria A
MA
Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Kenney
Anna M
AM
Sicinska
Ewa
E
Kalaszczynska
Ilona
I
Bronson
Roderick T
RT
Rowitch
David H
DH
Gardner
Humphrey
H
Sicinski
Piotr
P
D000749:Anemia, Megaloblastic / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002531:Cerebellum / Q000002:abnormalities* / Q000473:pathology; D019938:Cyclin D1 / Q000502:physiology*; D056742:Cyclin D2; D056743:Cyclin D3; D016213:Cyclins / Q000502:physiology*; D004622:Embryo, Mammalian / Q000002:abnormalities; D005314:Embryonic and Fetal Development; D005260:Female; D016259:Genes, myc; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009422:Nervous System Diseases / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D012333:RNA, Messenger; D016160:Retinoblastoma Protein / Q000378:metabolism; D012190:Retroviridae
C486196:Ccnd2 protein, mouse; C534697:Ccnd3 protein, mouse; D056742:Cyclin D2; D056743:Cyclin D3; D016213:Cyclins; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D019938:Cyclin D1