Abstract
Hox genes encode homeodomain-containing proteins that control embryonic development in multiple contexts. Up to 30 Hox genes, distributed among all four clusters, are expressed during mammalian kidney morphogenesis, but functional redundancy between them has made a detailed functional account difficult to achieve. We have investigated the role of the HoxD cluster through comparative molecular embryological analysis of a set of mouse strains carrying targeted genomic rearrangements such as deletions, duplications, and inversions. This analysis allowed us to uncover and genetically dissect the complex role of the HoxD cluster. Regulation of metanephric mesenchyme-ureteric bud interactions and maintenance of structural integrity of tubular epithelia are differentially controlled by some Hoxd genes during renal development, consistent with their specific expression profiles. We also provide evidence for a kidney-specific form of colinearity that underlies the differential expression of two distinct sets of genes located on both sides and overlapping at the Hoxd9 locus. These insights further our knowledge of the genetic control of kidney morphogenesis and may contribute to understanding certain congenital kidney malformations, including polycystic kidney disease and renal hypoplasia.
Highlights
Mammalian genomes contain 39 genes related to the Drosophila homeotic genes, which encode transcription factors necessary for proper development along the major body axis
Our set of genetic rearrangements allowed us to localize the position of regulatory sequences, which control the expression of these genes during kidney development
We show that the most striking kidney defect at birth is a failure of ureteric bud (UB) branching morphogenesis, leading to kidney hypoplasia associated with early postnatal death
Summary
Mammalian genomes contain 39 genes related to the Drosophila homeotic genes, which encode transcription factors necessary for proper development along the major body axis In the mouse, these Hox genes are organized in four separate chromosomal clusters and are expressed along the body axis in a spatio-temporal manner that corresponds to their physical positions along the clusters [1,2]. These Hox genes are organized in four separate chromosomal clusters and are expressed along the body axis in a spatio-temporal manner that corresponds to their physical positions along the clusters [1,2] Because these four clusters were generated by large-scale duplications, Hox genes are classified into thirteen groups of paralogy, based on both sequence similarities and respective positions along the clusters. In the developing mammalian urogenital system, simultaneous expression of about thirty Hox genes has been reported, and some traces of colinear regulation became apparent [5,6,7]
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