The aryl hydrocarbon receptor promotes differentiation during mouse preimplantational embryo development

Abstract

Mammalian embryogenesis is a complex process controlled by transcription factors that regulate the balance between pluripotency and differentiation. Transcription factor aryl hydrocarbon receptor (AhR) regulates OCT4/POU5F1 and NANOG, both essential controllers of pluripotency, stemness and early embryo development. Molecular mechanisms controlling OCT4/POU5F1 and NANOG during embryogenesis remain unidentified. We show that AhR regulates pluripotency factors and maintains the metabolic activity required for proper embryo differentiation. AhR-lacking embryos (AhR À/À ) showed a pluripotent phenotype characterized by a delayed expression of trophectoderm differentiation markers. Accordingly, central pluripotency factors OCT4/POU5F1 and NANOG were overexpressed in AhR À/À embryos at initial developmental stages. An altered intracellular localization of these factors was observed in the absence of AhR and, importantly, Oct4 had an opposite expression pattern with respect to AhR from the two-cell stage to blastocyst, suggesting a negative regulation of OCT4/POU5F by AhR. We propose that AhR is a regulator of pluripotency and differentiation in early mouse embryogenesis.

Aryl hydrocarbon receptor (AhR) reveals evidence of antagonistic pleiotropy in the regulation of the aging process

“…Ko et al [ 24 ] demonstrated that several pluripotency factors, i.e., OCT4, NANOG, and SOX2, were able to inhibit the expression of AhR gene in mouse ES cells by binding to the silencer domain of the AhR gene. Several other investigators have also revealed that the AhR gene needs to be repressed so that ES cells can maintain their mitotic progression and pluripotency [ 16 , 25 ]. For instance, OCT4 and NANOG factors displayed an overexpression in the mouse AhR −/− embryos inhibiting their differentiation process [ 16 ].…”

Aryl Hydrocarbon Receptor: From Homeostasis to Tumor Progression

“…In particular, the introduction of 4TFs (OCT4, SOX2, KLF4 and MYC) gives the necessary capacitation to revert differentiated fibroblasts into pluripotent stem cells, providing them with similar characteristics to embryonic stem cells ( Takahashi and Yamanaka, 2006 ). AHR has been presented as another TF involved in a variety of physiologic functions ( Fernandez-Salguero et al, 1995 ; Fernandez-Salguero et al, 1997 ; Mulero-Navarro and Fernandez-Salguero, 2016 ) that has been recently related with those Yamanaka factors in the regulation of pluripotency and differentiation state in early mouse embryogenesis ( Nacarino-Palma et al, 2021a ) and other differentiation and pluripotency processes ( Morales-Hernández et al, 2016 ; González-Rico et al, 2020 ; Rico-Leo et al, 2021 ). Several studies evidence that the activation of the genetic programs involved in embryogenesis are both critical and dominant in regeneration ( Fausett and Goldman, 2006 ; Lepilina et al, 2006 ; Ransom et al, 2018 ).…”

“…Moreover, AHR has a relevant role in the early stages of embryonic stem cell differentiation, regulating the core pluripotency network of transcription factors OCT4/POU5F1, NANOG, and SOX2 at initial developmental stages. The lack of AHR in early mouse embryos generates a delay in the expression of such differentiation markers, resulting in a more pluripotent state of AHR-null embryos ( Nacarino-Palma et al, 2021a ). Also, other studies have shown that AHR promotes the differentiation of human embryoid teratoma cells through inhibition of OCT4 and NANOG expression ( Morales-Hernández et al, 2016 ; González-Rico et al, 2020 ).…”

“…Moreover, Hippo signaling pathway, responsible for the first fate decision establishment in morula stage mouse embryos, was also upregulated in AHR −/− embryos, contributing to the differentiation of extra-embryonic tissues. In this context, AHR has a pro-differentiation role in the early mouse embryo needed to specify the different cell fates ( Nacarino-Palma et al, 2021a ).…”

Stem-Cell Theory of Cancer: Implications for Antiaging and Anticancer Strategies

“…AHR is a regulator of cytochrome P450, which metabolizes xenobiotic chemicals coming through our alimentary canal. Importantly, AHR displays stemness properties and dispenses stem-like functions because it regulates metabolic enzymes, moderates immunity, and balances stem cell pluripotency vs differentiation [ 50 , 51 ]. After all, AHR binds exogenous ligands, such as natural plant flavonoids, polyphenols, and indoles, that we ingest to feed ourselves, as well as to feed the microbiome in our guts.…”