Inactivation of FGF8 in early mesoderm reveals an essential role in kidney development.
To bypass the essential gastrulation function of Fgf8 and study its role in lineages of the primitive streak, we have used a new mouse line, T-Cre, to generate mouse embryos with pan-mesodermal loss of Fgf8 expression. Surprisingly, despite previous models in which Fgf8 has been assigned a pivotal role in segmentation/somite differentiation, Fgf8 is not required for these processes. However, mutant neonates display severe renal hypoplasia with deficient nephron formation. In mutant kidneys, aberrant cell death occurs within the metanephric mesenchyme (MM), particularly in the cortical nephrogenic zone, which provides the progenitors for recurring rounds of nephron formation. Prior to mutant morphological changes, Wnt4 and Lim1 expression, which is essential for nephrogenesis, is absent in MM. Furthermore, comparative analysis of Wnt4-null homozygotes reveals concomitant downregulation of Lim1 and diminished tubule formation. Our data support a model whereby FGF8 and WNT4 function in concert to induce the expression of Lim1 for MM survival and tubulogenesis.
Perantoni
Alan O
AO
Laboratory of Comparative Carcinogenesis, National Cancer Institute, NCI-Frederick, Frederick, MD 21702, USA.
Timofeeva
Olga
O
Naillat
Florence
F
Richman
Charmaine
C
Pajni-Underwood
Sangeeta
S
Wilson
Catherine
C
Vainio
Seppo
S
Dove
Lee F
LF
Lewandoski
Mark
M
D000483:Alleles; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002454:Cell Differentiation; D019070:Cell Lineage; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D060850:LIM-Homeodomain Proteins; D018878:Limb Buds / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors; D051153:Wnt Proteins; D060528:Wnt4 Protein
C496457:Fgf8 protein, mouse; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; C499523:Lhx1 protein, mouse; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D051153:Wnt Proteins; D060528:Wnt4 Protein; C555582:Wnt4 protein, mouse; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors