Redefining the Progression of Lineage Segregations during Mammalian Embryogenesis by Clonal Analysis

Although it is well established that neural cells are ectodermal derivatives in bilaterian animals, here we report the surprising discovery that some of the pharyngeal neurons of sea urchin embryos develop de novo from the endoderm. The appearance of these neurons is independent of mouth formation, in which the stomodeal ectoderm joins the foregut. The neurons do not derive from migration of ectoderm cells to the foregut, as shown by lineage tracing with the photoactivatable protein KikGR. Their specification and development depend on expression of Nkx3-2, which in turn depends on Six3, both of which are expressed in the foregut lineage. SoxB1, which is closely related to the vertebrate Sox factors that support a neural precursor state, is also expressed in the foregut throughout gastrulation, suggesting that this region of the fully formed archenteron retains an unexpected pluripotency. Together, these results lead to the unexpected conclusion that, within a cell lineage already specified to be endoderm by a well-established gene regulatory network [Peter IS, Davidson EH (2010) Dev Biol 340:188-199], there also operates a Six3/Nkx3-2-dependent pathway required for the de novo specification of some of the neurons in the pharynx. As a result, neuroendoderm precursors form in the foregut aided by retention of a SoxB1-dependent pluripotent state.cell fate specification | embryonic development | neurogenesis | enteric nerve

Section: Discussionmentioning

confidence: 82%

Direct development of neurons within foregut endoderm of sea urchin embryos

Wen-ling

Angerer

2011

“…Differences in single Tet3 vs. triple Tet KOs is most likely due to functional redundancy from the other two Tet family members, Tet1 and Tet2. In WT embryos, NMPs residing in the NSB and CLE contribute to both neural tube and paraxial mesoderm all along the AP body axis (24)(25)(26)(27) (Fig. 6 I, Left).…”

Section: Discussionmentioning

confidence: 99%

“…Population fate maps at early somite stages have identified two regions containing NMPs: the dorsal layer of the node-streak border (NSB) and the caudal lateral epiblast (CLE) on either side of the primitive streak (PS) (24)(25)(26)(27). In vitro, the induction of the neuroectoderm in ES cell (ESC) cultures is often referred to as the "default" pathway, because neuroectoderm readily develops in cultures that contain no serum or lack signaling through the Wnt, bone morphogenetic protein 4 (Bmp4), or activin signaling pathways (28)(29)(30).…”

Section: Significancementioning

confidence: 99%

Tet proteins influence the balance between neuroectodermal and mesodermal fate choice by inhibiting Wnt signaling

Yue

Pastor

et al. 2016

TET-family dioxygenases catalyze conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and oxidized methylcytosines in DNA. Here, we show that mouse embryonic stem cells (mESCs), either lacking Tet3 alone or with triple deficiency of Tet1/2/3, displayed impaired adoption of neural cell fate and concomitantly skewed toward cardiac mesodermal fate. Conversely, ectopic expression of Tet3 enhanced neural differentiation and limited cardiac mesoderm specification. Genome-wide analyses showed that Tet3 mediates cell-fate decisions by inhibiting Wnt signaling, partly through promoter demethylation and transcriptional activation of the Wnt inhibitor secreted frizzled-related protein 4 (Sfrp4). Tet1/2/3-deficient embryos (embryonic day 8.0–8.5) showed hyperactivated Wnt signaling, as well as aberrant differentiation of bipotent neuromesodermal progenitors (NMPs) into mesoderm at the expense of neuroectoderm. Our data demonstrate a key role for TET proteins in modulating Wnt signaling and establishing the proper balance between neural and mesodermal cell fate determination in mouse embryos and ESCs.

“…Secreted Wnts emanating from the primitive streak regulate the fate of posterior progenitors, including the neuromesodermal progenitor (NMP), an embryonic cell that depends upon Wnt3a for self-renewal and mesodermal differentiation and that gives rise to the spinal cord, dermis, and musculoskeletal system of the trunk and tail (4)(5)(6). Embryos lacking Wnt3a, Ctnnb1 (β-catenin), T-cell factor (Tcf) 1 and lymphoid enhancer factor (Lef) 1, or specificity protein (Sp) 5 and Sp8 display similar severe posterior truncations caused by the loss of NMPs (7)(8)(9)(10).…”

mentioning

confidence: 99%

Sp5 and Sp8 recruit β-catenin and Tcf1-Lef1 to select enhancers to activate Wnt target gene transcription

Kennedy

Chalamalasetty

Thomas

et al. 2016

The ancient, highly conserved, Wnt signaling pathway regulates cell fate in all metazoans. We have previously shown that combined null mutations of the specificity protein (Sp) 1/Klf-like zinc-finger transcription factors Sp5 and Sp8 (i.e., Sp5/8) result in an embryonic phenotype identical to that observed when core components of the Wnt/β-catenin pathway are mutated; however, their role in Wnt signal transduction is unknown. Here, we show in mouse embryos and differentiating embryonic stem cells that Sp5/8 are gene-specific transcriptional coactivators in the Wnt/β-catenin pathway. Sp5/8 bind directly to GC boxes in Wnt target gene enhancers and to adjacent, or distally positioned, chromatin-bound T-cell factor (Tcf) 1/lymphoid enhancer factor (Lef) 1 to facilitate recruitment of β-catenin to target gene enhancers. Because Sp5 is itself directly activated by Wnt signals, we propose that Sp5 is a Wnt/β-catenin pathway-specific transcripton factor that functions in a feed-forward loop to robustly activate select Wnt target genes.S ignaling pathways in multicellular organisms have evolved over millions of years to accommodate complex programs of tissue-specific gene expression. One such pathway, the Wnt/ β-catenin pathway, regulates gene expression by elevating the cytosolic levels of the transcription coactivator β-catenin (1). Stabilized β-catenin translocates to the nucleus, where it interacts with the DNA-bending, DNA-binding Tcf1 and Lef1 transcription factors (TFs), which subsequently replace Groucho/ Tcf3 repressor complexes on Wnt target gene enhancers (2). β-Catenin interacts with cell context-dependent cofactors (web. stanford.edu/group/nusselab/cgi-bin/wnt/) to associate with RNA polymerase II and the general transcription apparatus to activate transcription. However, the nature of the β-cateninTcf/Lef enhancer-binding protein complex and the mechanisms that facilitate its association with regulatory elements at Wnt target genes remain poorly understood.The formation of a Wnt signaling center during gastrulation is essential for animal development (3). Secreted Wnts emanating from the primitive streak regulate the fate of posterior progenitors, including the neuromesodermal progenitor (NMP), an embryonic cell that depends upon Wnt3a for self-renewal and mesodermal differentiation and that gives rise to the spinal cord, dermis, and musculoskeletal system of the trunk and tail (4-6). Embryos lacking Wnt3a, Ctnnb1 (β-catenin), T-cell factor (Tcf) 1 and lymphoid enhancer factor (Lef) 1, or specificity protein (Sp) 5 and Sp8 display similar severe posterior truncations caused by the loss of NMPs (7-10). These genes define a syn-phenotype group that, together with the genetic interactions observed between Sp5 and Wnt3a, suggests that Sp5/8 could be effectors of Wnt signaling. Sp5/8 are closely related to Sp1, which is one of the first identified eukaryotic TFs (11) and is frequently associated with the regulation of housekeeping genes. In contrast to the ubiquitously expressed Sp1, Sp5 expression is restricte...