Regulation of Axial Elongation by Cdx

Abstract

During mouse development, the primordia of the posterior body including the trunk and tail tissues of the embryo forms largely from a bipotential cell population that resides in the posterior growth zone in vertebrate embryos. This bipotential cell population contains neuromesodermal progenitors (NMP) which are found in the tail bud which replaces the primitive streak after gastrulation and contributes to axial elongation by the formation of both the spinal cord and paraxial mesoderm derivatives. The three vertebrate Cdx genes, Cdx1, Cdx2 and Cdx4, encode transcription factors that play important roles in axial elongation since the triple Cdx mutant embryos fail to generate any tissue posterior to the occipital primordia. A comparison of Cdx mutant phenotypes suggests that Cdx2 is the most important contributor to axial elongation since Cdx2 heterozygous mutants exhibit foreshortened tails and Cdx2 conditional mutants exhibit axial truncation and complete loss of tail bud structures. Cdx2 target genes, such as Wnt3a, Cyp26a1 and T, are also essential for axial elongation. Cdx1 null mutants are viable and exhibit homeosis of cervical and anterior thoracic vertebrae, while Cdx4 null mutants are phenotypically normal. In addition, it has been shown that simultaneous loss of multiple copies of Cdx alleles disrupts axial elongation more severely than each single mutation which suggests there is overlapping function among the Cdx family. The genetic network underlying regulation of axial elongation by the Cdx family is not fully understood due in part to this functional overlap. In this thesis, I employed a conditional Cre-loxP system to derive conditional mutants lacking all Cdx functions. Additionally, Pax2-GFP transgenic mice where GFP is expressed under the control of Pax2 locus were used to enrich tail bud NMP cells for RNA-seq and ChIP-seq analysis for Cdx2. Using this approach, I revealed new target genes and pathways that are regulated by Cdx members and likely involved in axial elongation.