The Role of E2f4 in Cell Cycle Exit and Bone Development

Members of the E2F family of transcription factors are critical downstream effectors of the pocket protein family and mediate the regulation of genes required for cellular proliferation. The repressive E2Fs act in association with the pocket proteins to promote a G0/G1 phase of the cell cycle. These complexes recruit histone deacetylases to target gene promoters to prevent the transcription of genes required for cell cycle progression. As cell cycle exit is often concomitant with differentiation, it is not surprising that mutation of the E2Fs and pocket proteins results in defective development and differentiation. Mutation of the most abundant E2F, E2F4, is known to disrupt the proper differentiation of several cell types, including erythrocytes and respiratory epithelium cells. Here, I analyzed a novel role for E2f4 in bone development. I found that mutation of E2f4 causes defects in intramembranous and endochondral bone development. The calvarial bones of the skull exhibit the most severe defect in development, which is caused by a significant delay in differentiation of osteoblasts. I showed that E2f4 loss does not alter the differentiation potential of osteoblast progenitors. Instead, loss of E2f4 impairs the ability of these cells to exit the cell cycle and increases the pool of undifferentiated progenitor cells, delaying bone formation. To further elucidate the role of E2f4 in cell cycle exit and differentiation, I have generated conditional E2f4 knockout mice. Analysis of these mice will address the cell autonomous roles E2f4 plays during differentiation and development, in addition to establish compensatory roles E2f4 may share with other E2F family members. Taken together, this work has established the in vivo role of E2f4 in osteoblast differentiation and bone development. Furthermore, this work opens new fields of study regarding E2f4 function during mouse development.

Year	Entry
1998	Yasuda H, Shima N, Akagawa NN, Yamaguchi K, Kinosaki M, Mochizuki S-I, Omoyasu AT, Yano K, Goto M, Murakami A, Tsuda E, Morinaga T, Igashio KH, Udagawa N, Tkahashi N, Suda T. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA. March 31, 1998;95(7):3597-3602.
1999	St-Jacques B, Hammerschmidt M, McMahon AP. Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev. August 15, 1999;13(16):2072-2086.
1997	Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsent G. Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell. May 30, 1997;89(5):747-754.
1999	Bi W, Deng JM, Zhang Z, Behringer RR, de Crombrugghe B. Sox9 is required for cartilage formation. Nat Genet. May 1999;22(1):85-89.
2005	Hill TP, Später D, Taketo MM, Birchmeier W, Hartmann C. Canonical Wnt/β-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev Cell. May 2005;8(5):727-738.
1997	Otto F, Thornell AP, Crompton T, Denzel A, Gilmour KC, Rosewell IR, Stamp GW, Beddington RS, Mundlos S, Olsen BR, Selby PB, Owen MJ. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell. May 30, 1997;89(5):765-771.
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Year

Entry

1998

Yasuda H, Shima N, Akagawa NN, Yamaguchi K, Kinosaki M, Mochizuki S-I, Omoyasu AT, Yano K, Goto M, Murakami A, Tsuda E, Morinaga T, Igashio KH, Udagawa N, Tkahashi N, Suda T. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA. March 31, 1998;95(7):3597-3602.

1999

St-Jacques B, Hammerschmidt M, McMahon AP. Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev. August 15, 1999;13(16):2072-2086.

1997

Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsent G. Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell. May 30, 1997;89(5):747-754.

1999

Bi W, Deng JM, Zhang Z, Behringer RR, de Crombrugghe B. Sox9 is required for cartilage formation. Nat Genet. May 1999;22(1):85-89.

2005

Hill TP, Später D, Taketo MM, Birchmeier W, Hartmann C. Canonical Wnt/β-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev Cell. May 2005;8(5):727-738.