Lhx1 functions together with Otx2, Foxa2, and Ldb1 to govern anterior mesendoderm, node, and midline development

Abstract

Gene regulatory networks controlling functional activities of spatially and temporally distinct endodermal cell populations in the early mouse embryo remain ill defined. The T-box transcription factor Eomes, acting downstream from Nodal/Smad signals, directly activates the LIM domain homeobox transcription factor Lhx1 in the visceral endoderm. Here we demonstrate Smad4/Eomes-dependent Lhx1 expression in the epiblast marks the entire definitive endoderm lineage, the anterior mesendoderm, and midline progenitors. Conditional inactivation of Lhx1 disrupts anterior definitive endoderm development and impedes node and midline morphogenesis in part due to severe disturbances in visceral endoderm displacement. Transcriptional profiling and ChIP-seq (chromatin immunoprecipitation [ChIP] followed by high-throughput sequencing) experiments identified Lhx1 target genes, including numerous anterior definitive endoderm markers and components of the Wnt signaling pathway. Interestingly, Lhx1-binding sites were enriched at enhancers, including the Nodal-proximal epiblast enhancer element and enhancer regions controlling Otx2 and Foxa2 expression. Moreover, in proteomic experiments, we characterized a complex comprised of Lhx1, Otx2, and Foxa2 as well as the chromatin-looping protein Ldb1. These partnerships cooperatively regulate development of the anterior mesendoderm, node, and midline cell populations responsible for establishment of the left-right body axis and head formation.

The p53 Family Coordinates Wnt and Nodal Inputs in Mesendodermal Differentiation of Embryonic Stem Cells

“…FoxA2 expression was interrupted in the midline of E7.75 TKO chimeras (Figure S2C), reminiscent of defects observed in mutants of Lhx1, a downstream target of nodal-Smad signaling (Costello et al, 2015). In E7.25 chimeras mCherry+ TKO cells failed to induce FoxA2 expression whereas surrounding WT cells expressed high levels of FoxA2 (Figure 2C), reinforcing the conclusion that TKO cells were unable to trigger mesendoderm specification.…”

The LDB1 Complex Co-opts CTCF for Erythroid Lineage-Specific Long-Range Enhancer Interactions

“…Although the number is likely to be an overestimate due to the non-exhaustive list of erythroid genes, we suggest that LDB1-bound enhancers have functions beyond those related to erythroid genes. Indeed, recent reports describe LDB1 involvement in long-range gene regulation in select non-erythroid cells (Caputo et al, 2015; Zhang et al, 2015; Costello et al, 2015). Although molecular details remain to be worked out, in these cases LIM only or LIM-homeodomain proteins and DNA binding factors distinct from those in erythroid cells likely mediate LDB1 interaction with DNA.…”

Prenatal diagnosis of 17q12 deletion syndrome: from fetal hyperechogenic kidneys to high risk for autism

“…Within the 17q12 deletions, another putative candidate gene for the neurodevelopmental abnormalities is the Lim Homeobox 1 (LHX1). LHX1 was shown to play a role in transcriptional control of axonal guidance and the differentiation of neural cells and in early mouse embryos was shown to regulate head formation . In humans, pathogenic variants in LHX1 have been described in individuals with Müllerian aplasia/Mayer–Rokitansky–Küster–Hauser syndrome …”