The developing kidney offers a powerful model system for studying the principles of mammalian development, with inductive interactions between the ureteric bud and metanephric mesenchyme, conversion of mesenchyme into epithelia, branching morphogenesis and proximal-distal segmentation of the nephron. This is a proposal to study the functions of the Abd-B type Hox genes, and the Lim1 homeobox gene in the development of the metanephric mesenchyme. It is known that Hoxa 11 and Hoxd 11 are expressed in the metanephric mesenchyme and are required for normal branching morphogenesis. The Lim1 gene is expressed first in the intermediate mesoderm, then in the nephric duct, and later in the induced metanephric mesenchyme.
Specific aim 1 examines the functional relationships of the many Hox genes expressed during kidney development. One model predicts that Hox quantity is more important than Hox quality, while another predicts distinct patterning functions for different Hox genes. We propose to create an atlas of Abd-B Hox expression in the developing kidney to define regions of overlap and to determine if patterns are consistent with a proximal-distal patterning function in the nephron. We further propose a series of homeobox swap experiments that will test models of Hox function and provide a measure of overlap of downstream targets.
Specific aim 2 uses the Hoxa 11 promoter driving Cre expression to create a metanephric mesenchyme specific knockout of the Lim1 gene. A null mutation of Lim1 blocks differentiation of the early intermediate mesoderm, resulting in the absence of kidneys and gonads.
This aim will define the function of Lim1 in the differentiation of the metanephric mesenchyme.
Specific aim 3 identifies and studies the downstream targets of Hoxa 11 and Lim1. To better understand their function it is necessary to characterize the downstream effector genes they regulate. The proposed strategy uses developmentally appropriate cell lines and gene chips. Initial screens have found two targets of particular interest, alpha-beta integrin and Nov. We propose to confirm these targets, to determine if they are direct or indirect, and to identify additional downstream genes responsive to Hoxa 11 or Lim1 expression.
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