Changes in global gene expression patterns during development and maturation of the rat kidney

Abstract

We set out to define patterns of gene expression during kidney organogenesis by using high-density DNA array technology. Expression analysis of 8,740 rat genes revealed five discrete patterns or groups of gene expression during nephrogenesis. Group 1 consisted of genes with very high expression in the early embryonic kidney, many with roles in protein translation and DNA replication. Group 2 consisted of genes that peaked in midembryogenesis and contained many transcripts specifying proteins of the extracellular matrix. Many additional transcripts allied with groups 1 and 2 had known or proposed roles in kidney development and included LIM1, POD1, GFRA1, WT1, BCL2, Homeobox protein A11, timeless, pleiotrophin, HGF, HNF3, BMP4, TGF-␣, TGF-␤2, IGF-II, met, FGF7, BMP4, and ganglioside-GD3. Group 3 consisted of transcripts that peaked in the neonatal period and contained a number of retrotransposon RNAs. Group 4 contained genes that steadily increased in relative expression levels throughout development, including many genes involved in energy metabolism and transport. Group 5 consisted of genes with relatively low levels of expression throughout embryogenesis but with markedly higher levels in the adult kidney; this group included a heterogeneous mix of transporters, detoxification enzymes, and oxidative stress genes. The data suggest that the embryonic kidney is committed to cellular proliferation and morphogenesis early on, followed sequentially by extracellular matrix deposition and acquisition of markers of terminal differentiation. The neonatal burst of retrotransposon mRNA was unexpected and may play a role in a stress response associated with birth. Custom analytical tools were developed including ''The Equalizer'' and ''eBlot,'' which contain improved methods for data normalization, significance testing, and data mining.

Transcript profiling of Wilms tumors reveals connections to kidney morphogenesis and expression patterns associated with anaplasia

“…This supports the validity of using a pooled fetal kidney sample. Through comparison with a rat kidney development data set (Stuart et al, 2001), we found that 36 of 50 genes (72%) upregulated in Wilms tumors are more abundantly expressed in the early stages of kidney development. In contrast, 67 of 82 genes (82%) downregulated in Wilms tumors are preferentially expressed in the later stages of kidney development.…”

“…Notably, some genes in Category 2 (such as APOE and TIEG) and all genes in Category 3 have been classified as early or late nephrogenic genes by expression profiling (Stuart et al, 2001). Owing to the putative linkage of Wilms tumor to nephrogenesis, potential roles in normal kidney development for genes in these categories could be explored further.…”

“…edu/cgi-bin/source/sourceSearch), and have been implicated in Wilms tumor or other cancers. Category 3 includes genes that have not been definitively stated to be involved in development in the GeneReports compiled by the SOURCE program, but whose mRNA levels changed during rat nephrogenesis as measured by global gene expression profiling (Stuart et al, 2001) and have been implicated in Wilms tumor. For those genes in Category 1 that are implicated in kidney development, it appears that the genes we found to be overexpressed in Wilms tumors tend to be expressed higher in the metanephric mesenchyme (MM) than in the ureteric bud (UB) or UB branching derivatives, and their expression levels decrease as the MM differentiates.…”

“…A cDNA clone was considered upregulated (or downregulated) in Wilms tumors if its expression fulfilled the following two criteria: (a) intensities in the tumors (or in fetal kidney) above 300, called present and expressed at >1.5-fold higher (or lower), in at least 16 of the 31 tumor/fetal kidney comparisons; (b) one sample t-test two-sided P-value o0.01. Data for temporal gene expression patterns during rat kidney development were downloaded from http://organogenesis.ucsd.edu/data.html (Stuart et al, 2001). Current gene information and human homologs for the rat genes in the temporal expression patterns (Stuart et al, 2001) were obtained from recently updated Affymetrix databases (www.affymetrix.com/analysis/ index.affx).…”

Definition and spatial annotation of the dynamic secretome during early kidney development

“…Sixteen of the outliers from the microarray experiments have previously been implicated in kidney development in extensive expression profiling studies performed in mouse and rat by Schwab et al (2003) and Stuart et al (2001), respectively (e.g., midkine, Cxcl12, and Wnt-4). In addition, six other factors have been documented in the literature to be involved in kidney development, again providing independent verification of our data.…”