TY - JOUR
T1 - Hoxd11 specifies a program of metanephric kidney development within the intermediate mesoderm of the mouse embryo
AU - Mugford, Joshua W.
AU - Sipilä, Petra
AU - Kobayashi, Akio
AU - Behringer, Richard R.
AU - McMahon, Andrew P.
N1 - Funding Information:
We thank Denis Duboule for the gift of full-length mouse Hoxd11 cDNA. P.S. was funded by grants from the Finnish Academy (#107827), Helsingin Sanomain 100-vuotis and Alfred Kordelin Foundations. R.R.B was funded by NIH grant HD30284. Work in A.P.M.'s laboratory is supported by NIH grant DK054364.
PY - 2008/7/15
Y1 - 2008/7/15
N2 - The mammalian kidney consists of an array of tubules connected to a ductal system that collectively function to control water/salt balance and to remove waste from the organisms' circulatory system. During mammalian embryogenesis, three kidney structures form within the intermediate mesoderm. The two most anterior structures, the pronephros and the mesonephros, are transitory and largely non-functional, while the most posterior, the metanephros, persists as the adult kidney. We have explored the mechanisms underlying regional specific differentiation of the kidney forming mesoderm. Previous studies have shown a requirement for Hox11 paralogs (Hoxa11, Hoxc11 and Hoxd11) in metanephric development. Mice lacking all Hox11 activity fail to form metanephric kidney structures. We demonstrate that the Hox11 paralog expression is restricted in the intermediate mesoderm to the posterior, metanephric level. When Hoxd11 is ectopically activated in the anterior mesonephros, we observe a partial transformation to a metanephric program of development. Anterior Hoxd11+ cells activate Six2, a transcription factor required for the maintenance of metanephric tubule progenitors. Additionally, Hoxd11+ mesonephric tubules exhibit an altered morphology and activate several metanephric specific markers normally confined to distal portions of the functional nephron. Collectively, our data support a model where Hox11 paralogs specify a metanephric developmental program in responsive intermediate mesoderm. This program maintains tubule forming progenitors and instructs a metanephric specific pattern of nephron differentiation.
AB - The mammalian kidney consists of an array of tubules connected to a ductal system that collectively function to control water/salt balance and to remove waste from the organisms' circulatory system. During mammalian embryogenesis, three kidney structures form within the intermediate mesoderm. The two most anterior structures, the pronephros and the mesonephros, are transitory and largely non-functional, while the most posterior, the metanephros, persists as the adult kidney. We have explored the mechanisms underlying regional specific differentiation of the kidney forming mesoderm. Previous studies have shown a requirement for Hox11 paralogs (Hoxa11, Hoxc11 and Hoxd11) in metanephric development. Mice lacking all Hox11 activity fail to form metanephric kidney structures. We demonstrate that the Hox11 paralog expression is restricted in the intermediate mesoderm to the posterior, metanephric level. When Hoxd11 is ectopically activated in the anterior mesonephros, we observe a partial transformation to a metanephric program of development. Anterior Hoxd11+ cells activate Six2, a transcription factor required for the maintenance of metanephric tubule progenitors. Additionally, Hoxd11+ mesonephric tubules exhibit an altered morphology and activate several metanephric specific markers normally confined to distal portions of the functional nephron. Collectively, our data support a model where Hox11 paralogs specify a metanephric developmental program in responsive intermediate mesoderm. This program maintains tubule forming progenitors and instructs a metanephric specific pattern of nephron differentiation.
KW - Hox genes
KW - Hoxd11
KW - Kidney
KW - Mesonephros
KW - Metanephros
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U2 - 10.1016/j.ydbio.2008.03.044
DO - 10.1016/j.ydbio.2008.03.044
M3 - Article
C2 - 18485340
AN - SCOPUS:46049114472
SN - 0012-1606
VL - 319
SP - 396
EP - 405
JO - Developmental Biology
JF - Developmental Biology
IS - 2
ER -