The vertebrate caudal proteins, being upstream regulators of the Hox genes, play a role in establishment of the body plan. We describe analysis of two orthologous caudal genes (chick cdx-A and mouse cdx-1) by use of lacZ reporters expressed in transgenic mouse embryos. The expression patterns show many similarities to the expression of endogenous mouse cdx-1. At 8.7 days, cdx/lacZ activity within neurectoderm and mesoderm forms posterior-to-anterior gradients, and we discuss the possibility that similar gradients of cdx gene expression may function as morphogen gradients for the establishment of Hox gene expression boundaries. Our observations suggest that gradients form by decay of cdx/lacZ activity in cells that have moved anterior to the vicinity of the node. The cdx-A/lacZ expression pattern requires an intron enhancer that includes two functional control elements: a DR2-type retinoic acid response element and a Tcf/beta-catenin binding motif. These motifs are structurally conserved in mouse cdx-1.
A systematic analysis of parthenogenetic (PG) cell fate within the central nervous system (CNS) was made throughout fetal development and neonatal and adult life. Chimeras were made between PG embryos carrying a ubiquitously expressed lacZ transgene and normal fertilized embryos. After detailed histological analysis, we find that the developmental potential of PG cells is spatially restricted to certain parts of the brain. PG cells are prevalent in telencephalic structures and are largely excluded from diencephalic structures, especially the hypothalamus. These spatial restrictions are established early in development. Behavioral studies with chimeras identified an increase in male aggression when the proportion of PG cells in the brain was high. These studies demonstrate that imprinted genes play key roles in development of the CNS and may be involved in behavior.
To investigate the link between Cdx protein concentration and axial patterning in embryos, we made lines of mice OE1, OE2 and OE4 that overexpress each of the Cdx genes Cdx1, Cdx2 and Cdx4, respectively. The lines carry Cdx transgenes under the transcriptional control of their own promoter/enhancer elements. Transgenic embryos show Cdx transcription at 8.5 to 8.7 days within normal spatial domains for Cdx expression (primitive streak/tailbud), yet, overall, they contain elevated levels of Cdx proteins. Increased doses of Cdx proteins result in homeotic shifts in vertebral types along most of the vertebral column, with transformations being most obvious within the cervical region. Most of the shifts are anterior-to-posterior transformations and the anterior limits of these are commonly skull/vertebra 1 (v1) for OE1, v1/v2 for OE2 and v7 for OE4. OE embryos display anterior shifts in the expression of a Hoxa7/lacZ reporter within neural, paraxial and lateral plate mesoderm tissues. Hoxa7/lacZ expression commences at the normal time in OE1 and OE4 embryos. OE2 embryos display a forward shift in the gradient of Cdx2 protein along the axis, suggesting that a Cdx morphogen gradient model could account, at least in part, for the homeotic shifts in vertebral types. OE mice display additional defects: forelimb deficiencies in OE1, multiple tail axes, vertebral mis-alignments and axial truncations in OE2.
Following gastrulation, the three primary germ layers develop into the major organs in a process known as organogenesis. Single-cell RNA sequencing has enabled the profiling of the gene expression dynamics of these cell fate decisions, yet a comprehensive map of the interplay between transcription factors and cis-regulatory elements is lacking, as are the underlying gene regulatory networks. Here we generate a multi-omics atlas of mouse early organogenesis by simultaneously profiling gene expression and chromatin accessibility from tens of thousands of single cells. We develop a computational method to leverage the multi-modal readouts to predict transcription factor binding events in cis-regulatory elements, which we then use to infer gene regulatory networks that underpin lineage commitment events. Finally, we show that these models can be used to generate in silico predictions of the effect of transcription factor perturbations. We validate this experimentally by showing that Brachyury is essential for the differentiation of neuromesodermal progenitors to somitic mesoderm fate by priming cis-regulatory elements.
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