The promyelocytic leukaemia zinc finger (Plzf) protein (encoded by the gene Zfp145) belongs to the POZ/zinc-finger family of transcription factors. Here we generate Zfp145−/− mice and show that Plzf is essential for patterning of the limb and axial skeleton. Plzf inactivation results in patterning defects affecting all skeletal structures of the limb, including homeotic transformations of anterior skeletal elements into posterior structures. We demonstrate that Plzf acts as a growth-inhibitory and pro-apoptotic factor in the limb bud. The expression of members of the abdominal b (Abdb) Hox gene complex, as well as genes encoding bone morphogenetic proteins (Bmps), is altered in the developing limb of Zfp145−/− mice. Plzf regulates the expression of these genes in the absence of aberrant polarizing activity and independently of known patterning genes. Zfp145−/− mice also exhibit anterior-directed homeotic transformation throughout the axial skeleton with associated alterations in Hox gene expression. Plzf is therefore a mediator of anterior-to-posterior (AP) patterning in both the axial and appendicular skeleton and acts as a regulator of Hox gene expression.
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We thank D. Ruggero and S. Pizette for discussions; M. Branford and C. Kaduro for help with experiments; J.H. Dong and V. Soares for help with the generation and the management of the Zfp145 mutants; N. Lampin and B. Gumbiner for help and advice with the electron scanning microscopy analysis; D. Duboule and P. Gruss for Hoxd and Hoxa probes, respectively; M. Scott and A. Joyner for Ptch and Gli probes, respectively; M. Capecchi and A. Boulet for Hoxc6 and Hoxc8 probes; and P.G. Pelicci and M. Ruthardt for a PLZF antibody and probe. P.P.P. is a Scholar of the Leukemia and Lymphoma Society (formerly known as the Leukemia Society of America). L.N. is an Assistant Investigator of the Howard Hughes Medical Institute. This work was supported by the NIH (CA-08748 and CA-71692 awarded to Sloan-Kettering Institute and P.P.P.).
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