Abstract
The uterus is a remarkable organ that must guard against infections while maintaining the ability to support growth of a fetus without rejection. The Hoxa10 and Hoxa11 genes have previously been shown to play essential roles in uterus development and function. In this report we show that the Hoxa9,10,11, Hoxc9,10,11, Hoxd9,10,11 genes play a redundant role in the formation of uterine glands. In addition, we use single cell RNA-seq to create a high resolution gene expression atlas of the developing wild type mouse uterus. Cell types and subtypes are defined, for example dividing endothelial cells into arterial, venous, capillary, and lymphatic, while epithelial cells separate into luminal and glandular subtypes. Further, a surprising heterogeneity of stromal and myocyte cell types are identified. Transcription factor codes and ligand/receptor interactions are characterized. We also used single cell RNA-seq to globally define the altered gene expression patterns in all developing uterus cell types for two Hox mutants, with 8 or 9 mutant Hox genes. The mutants show a striking disruption of Wnt signaling as well as the Cxcl12/Cxcr4 ligand/receptor axis.
Highlights
The uterus must guard against infections while receiving a semi-allograft implant, the embryo, without rejection
In this report we extend this approach to search for possible female fertility functions for the Hoxc[9,10,11] genes
In this report we show that Hoxc[9,10,11] genes have redundant function with Hoxa[9,10,11] and Hoxd[9,10,11] in uterine gland formation
Summary
The uterus must guard against infections while receiving a semi-allograft implant, the embryo, without rejection. The closely related Hox[9] paralog genes could be mutated in combination, such as Hoxa9−/− Hoxb9−/− Hoxd9−/−, with the resulting triple homozygous mutant mice having normal uterus function, their mammary www.nature.com/scientificreports/. Mice with multiple combinations of mutations of either the Hox[10] or Hox[11] paralog groups have interesting kidney and limb abnormalities, but no described infertility phenotypes extending beyond those associated with the Hoxa[10] and Hoxa[11] genes[23,24] These results suggest unique roles for Hoxa[10] and Hoxa[11] in uterus development and function. In this report we show that Hoxc[9,10,11] genes have redundant function with Hoxa[9,10,11] and Hoxd[9,10,11] in uterine gland formation
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