Aryl hydrocarbon receptor deletion in cerebellar granule neuron precursors impairs neurogenesis

Dever, Daniel P.; Adham, Zachariah O.; Thompson, Bryan D.; Genestine, Matthieu; Cherry, Jonathan D.; Olschowka, John A.; DiCicco‐Bloom, Emanuel; Opanashuk, Lisa A.

doi:10.1002/dneu.22330

Cited by 39 publications

(30 citation statements)

References 66 publications

(100 reference statements)

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“…To investigate the role of the AHR pathway in neural progenitor fate in the developing cerebellum, we conditionally deleted the Ahr gene from Math1+ GCPs during cerebellar development. In agreement with a previous report 24 , we observed reduced GCP proliferation and enhanced cell cycle exit (as measured by cell Q fraction) ( Fig. S1a) of GCPs in Ahr conditional knockout Math1cre; Ahr f/f (Ahr cKO) cerebella, compared to control Ahr f/f cerebella (Fig.…”

Section: Ahr Modulates Primary Mouse Gcp Proliferation and Differentisupporting

confidence: 93%

The AHR pathway represses TGFβ-SMAD3 signalling and has a potent tumour suppressive role in SHH medulloblastoma

Sarić

Selby

Ramaswamy

et al. 2020

Sci Rep

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Sonic Hedgehog (SHH) medulloblastomas are brain tumours that arise in the posterior fossa. Cancerpropagating cells (CPCs) provide a reservoir of cells capable of tumour regeneration and relapse post-treatment. Understanding and targeting the mechanisms by which CPCs are maintained and expanded in SHH medulloblastoma could present novel therapeutic opportunities. We identified the aryl hydrocarbon receptor (AHR) pathway as a potent tumour suppressor in a SHH medulloblastoma mouse model. Ahr-deficient tumours and CPCs grown in vitro, showed elevated activation of the tGfβ mediator, SMAD3. Pharmacological inhibition of the TGFβ/SMAD3 signalling axis was sufficient to inhibit the proliferation and promote the differentiation of Ahr-deficient CPCs. Human SHH medulloblastomas with high expression of the AHR repressor (AHRR) exhibited a significantly worse prognosis compared to AHRR low tumours in two independent patient cohorts. Together, these findings suggest that reduced AHR pathway activity promotes SHH medulloblastoma progression, consistent with a tumour suppressive role for AHR. We propose that TGFβ/SMAD3 inhibition may represent an actionable therapeutic approach for a subset of aggressive SHH medulloblastomas characterised by reduced AHR pathway activity. Medulloblastoma represents one of the most common forms of paediatric, malignant brain tumours accounting for around 20% of all paediatric tumours of the CNS 1. Typical treatment consists of a combination of chemotherapy, surgical resection and neuraxis irradiation, with a cure rate of approximately 70-75% in children ≥3 years of age 2. However, survivors of medulloblastoma are left with a host of long-term adverse sequelae, including cognitive deficits, problems with neuroendocrine function and fertility 3,4. These drawbacks to traditional treatment options necessitate more effective patient stratification strategies based on biomarkers that predict outcome and identify specific molecular medulloblastoma subtypes for personalized, targeted therapies. Efforts to dissect the molecular underpinnings of medulloblastoma have identified four main subgroups-WNT, Sonic hedgehog (SHH), Group 3 and Group 4-with distinct transcriptional, DNA methylation and mutational profiles, and different clinical characteristics and outcomes 5-7. These subgroups are associated with different cells of origin 8. SHH tumours originate from cerebellar granule cell progenitors (GCPs), and display excessive activation of the SHH signalling pathway 9. The prognosis of SHH subgroup medulloblastomas is mixed, with

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Section: Ahr Modulates Primary Mouse Gcp Proliferation and Differentisupporting

confidence: 93%

The AHR pathway represses TGFβ-SMAD3 signalling and has a potent tumour suppressive role in SHH medulloblastoma

Sarić

Selby

Ramaswamy

et al. 2020

Sci Rep

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“…Possible roles of AHR in sensory/neural systems are less well understood in vertebrate animals, but results from AHR loss-of-function studies and effects of TCDD on neural development in fish and mammals [96–103] suggest that this is an area worth further exploration. For example, roles for AHR in developing GABAergic systems and in controlling dendrite growth may be shared by vertebrate and invertebrate species [36,37,96,99,102,104]. …”

Section: Functional Divergence Of a Pleiotropic Protein: Shared Anmentioning

confidence: 99%

Diversity as opportunity: Insights from 600 million years of AHR evolution

Hahn

Karchner

Merson

2017

Current Opinion in Toxicology

107

111

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The aryl hydrocarbon receptor (AHR) was for many years of interest only to pharmacologists and toxicologists. However, this protein has fundamental roles in biology that are being revealed through studies in diverse animal species. The AHR is an ancient protein. AHR homologs exist in most major groups of modern bilaterian animals, including deuterostomes (chordates, hemichordates, echinoderms) and the two major clades of protostome invertebrates [ecdysozoans (e.g. arthropods and nematodes) and lophotrochozoans (e.g. molluscs and annelids)]. AHR homologs also have been identified in cnidarians such as the sea anemone Nematostella and in the genome of Trichoplax, a placozoan. Bilaterians, cnidarians, and placozoans form the clade Eumetazoa, whose last common ancestor lived approximately 600 million years ago (MYA). The presence of AHR homologs in modern representatives of all these groups indicates that the original eumetazoan animal possessed an AHR homolog. Studies in invertebrates and vertebrates reveal parallel functions of AHR in the development and function of sensory neural systems, suggesting that these may be ancestral roles. Vertebrate animals are characterized by the expansion and diversification of AHRs, via gene and genome duplications, from the ancestral protoAHR into at least five classes of AHR-like proteins: AHR, AHR1, AHR2, AHR3, and AHRR. The evolution of multiple AHRs in vertebrates coincided with the acquisition of high-affinity binding of halogenated and polynuclear aromatic hydrocarbons and the emergence of adaptive functions involving regulation of xenobiotic-metabolizing enzymes and roles in adaptive immunity. The existence of multiple AHRs may have facilitated subfunction partitioning and specialization of specific AHR types in some taxa. Additional research in diverse model and non-model species will continue to enrich our understanding of AHR and its pleiotropic roles in biology and toxicology.

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“…Previous studies have linked AhR signaling to neuronal differentiation, neuronal migration, axonal branching, and dendritic arborization in C . elegans and Drosophila [ 21 – 23 ] as well as to the regulation of dendritic morphology in subneocortical hippocampal pyramidal and olfactory granule neurons [ 37 , 48 ] and to cerebellar neurogenesis [ 24 ]. Expression of AhR transcripts has been reported in rodent brain regions, including the cerebral cortex and hippocampus [ 16 , 17 ].…”

Section: Discussionmentioning

confidence: 99%

“…Spineless , the Drosophila homolog of the mammalian AhR, controls the complexity of dendritic arborization in sensory neuron subtypes [ 23 ]. In the mouse cerebellum, AhR has been shown to regulate granule cell neurogenesis [ 24 ]. Thus, it is plausible that AhR-mediated signaling regulates neuronal differentiation and maturation in the mammalian cerebral cortex.…”

Section: Introductionmentioning

confidence: 99%

Impaired dendritic growth and positioning of cortical pyramidal neurons by activation of aryl hydrocarbon receptor signaling in the developing mouse

et al. 2017

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The basic helix-loop-helix (bHLH) transcription factors exert multiple functions in mammalian cerebral cortex development. The aryl hydrocarbon receptor (AhR), a member of the bHLH-Per-Arnt-Sim subfamily, is a ligand-activated transcription factor reported to regulate nervous system development in both invertebrates and vertebrates, but the functions that AhR signaling pathway may have for mammalian cerebral cortex development remains elusive. Although the endogenous ligand involved in brain developmental process has not been identified, the environmental pollutant dioxin potently binds AhR and induces abnormalities in higher brain function of laboratory animals. Thus, we studied how activation of AhR signaling influences cortical development in mice. To this end, we produced mice expressing either constitutively active-AhR (CA-AhR), which has the capacity for ligand-independent activation of downstream genes, or AhR, which requires its ligands for activation. In brief, CA-AhR-expressing plasmid and AhR-expressing plasmid were each transfected into neural stems cells in the developing cerebrum by in utero electroporation on embryonic day 14.5. On postnatal day 14, mice transfected in utero with CA-AhR, but not those transfected with AhR, exhibited drastically reduced dendritic arborization of layer II/III pyramidal neurons and impaired neuronal positioning in the developing somatosensory cortex. The effects of CA-AhR were observed for dendrite development but not for the commissural fiber projection, suggesting a preferential influence on dendrites. The present results indicate that over-activation of AhR perturbs neuronal migration and morphological development in mammalian cortex, supporting previous observations of impaired dendritic structure, cortical dysgenesis, and behavioral abnormalities following perinatal dioxin exposure.

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Aryl hydrocarbon receptor deletion in cerebellar granule neuron precursors impairs neurogenesis

Cited by 39 publications

References 66 publications

The AHR pathway represses TGFβ-SMAD3 signalling and has a potent tumour suppressive role in SHH medulloblastoma

The AHR pathway represses TGFβ-SMAD3 signalling and has a potent tumour suppressive role in SHH medulloblastoma

Diversity as opportunity: Insights from 600 million years of AHR evolution

Impaired dendritic growth and positioning of cortical pyramidal neurons by activation of aryl hydrocarbon receptor signaling in the developing mouse

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