Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts.
Id proteins may control cell differentiation by interfering with DNA binding of transcription factors. Here we show that targeted disruption of the dominant negative helix-loop-helix proteins Id1 and Id3 in mice results in premature withdrawal of neuroblasts from the cell cycle and expression of neural-specific differentiation markers. The Id1-Id3 double knockout mice also display vascular malformations in the forebrain and an absence of branching and sprouting of blood vessels into the neuroectoderm. As angiogenesis both in the brain and in tumours requires invasion of avascular tissue by endothelial cells, we examined the Id knockout mice for their ability to support the growth of tumour xenografts. Three different tumours failed to grow and/or metastasize in Id1+/- Id3-/- mice, and any tumour growth present showed poor vascularization and extensive necrosis. Thus, the Id genes are required to maintain the timing of neuronal differentiation in the embryo and invasiveness of the vasculature. Because the Id genes are expressed at very low levels in adults, they make attractive new targets for anti-angiogenic drug design.
Lyden
D
D
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Young
A Z
AZ
Zagzag
D
D
Yan
W
W
Gerald
W
W
O'Reilly
R
R
Bader
B L
BL
Hynes
R O
RO
Zhuang
Y
Y
Manova
K
K
Benezra
R
R
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D001921:Brain / Q000098:blood supply / Q000196:embryology / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D018257:Helix-Loop-Helix Motifs; D051798:Inhibitor of Differentiation Protein 1; D039482:Integrin alpha5; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply*; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D009474:Neurons / Q000166:cytology*; D012097:Repressor Proteins; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D039482:Integrin alpha5; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D020778:Matrix Metalloproteinase 2