Targeted deletion of the mouse POU domain gene Brn-3a causes selective loss of neurons in the brainstem and trigeminal ganglion, uncoordinated limb movement, and impaired suckling.

Abstract

The aryl hydrocarbon receptor (AHR) belongs to the PAS (PER-ARNT-SIM) family transcription factors and mediates broad responses to numerous environmental pollutants and cellular metabolites, modulating diverse biological processes from adaptive metabolism, acute toxicity, to normal physiology of vascular and immune systems. The AHR forms a transcriptionally active heterodimer with ARNT (AHR nuclear translocator), which recognizes the dioxin response element (DRE) in the promoter of downstream genes. We determined the crystal structure of the mammalian AHR-ARNT heterodimer in complex with the DRE, in which ARNT curls around AHR into a highly intertwined asymmetric architecture, with extensive heterodimerization interfaces and AHR interdomain interactions. Specific recognition of the DRE is determined locally by the DNA-binding residues, which discriminates it from the closely related hypoxia response element (HRE), and is globally affected by the dimerization interfaces and interdomain interactions. Changes at the interdomain interactions caused either AHR constitutive nuclear localization or failure to translocate to nucleus, underlying an allosteric structural pathway for mediating ligand-induced exposure of nuclear localization signal. These observations, together with the global higher flexibility of the AHR PAS-A and its loosely packed structural elements, suggest a dynamic structural hierarchy for complex scenarios of AHR activation induced by its diverse ligands.he aryl hydrocarbon receptor (AHR) belongs to the PER-ARNT-SIM (PAS) family transcription factor that mediates broad responses to cellular and environmental cues. The AHR has been shown to be activated by diverse environmental toxicants and endogenous ligands, and play an important role in adaptive metabolism, dioxin toxicity, and normal vascular and immune development (1, 2), ever since it was identified four decades ago for mediating metabolic responses to aryl hydrocarbon toxicants (3, 4) and the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (5). The AHR was more recently found to mediate diverse cellular and physiological responses and likely respond to unknown endogenous AHR ligands (1, 2, 6-8). Developmentally, the AHR plays a role in the normal development and function of both the vascular and immune systems (9-12), and has close links to cancer, metabolic, immune, and cardiovascular diseases (13-18).Intense efforts in the past four decades have yielded important insights into the molecular processes governing AHR signaling. Newly synthesized AHR is located in cytosol and associated with the chaperones Hsp90 (19), P23 (20, 21), and AHR associated protein 9 (ARA9, also known as XAP2 or AIP) (22-24). Binding of ligands induces conformational changes in the AHR that lead to exposure of nuclear localization sequences (NLS) (25, 26). Following nuclear translocation, the AHR exchanges chaperones for a transcription partner, ARNT (1) and the AHR-ARNT heterodimer binds near the promoters of target genes at dioxin-response element (DRE...

Dach1 Mutant Mice Bear No Gross Abnormalities in Eye, Limb, and Brain Development and Exhibit Postnatal Lethality

“…Our data indicate that homozygous mutants die within the first 24 h and fail to suckle. Brn-3a and NMDA e2 receptor knockout mice exhibit similar phenotypes (23,39). However, impaired suckling in these mutants was also associated with both a decreased number of neurons in the trigeminal ganglion and the absence of a suckling response.…”

Coordinated regulation of gene expression by Brn3a in developing sensory ganglia

“…Targeted mutations in mice have shown that Brn3a is necessary for the correct development and/or survival of neurons in the sensory ganglia and some CNS nuclei (McEvilly et al, 1996;Xiang et al, 1996). Sensory neuron death in Brn3a knockout mice is preceded by loss of neurotrophin receptor expression (Huang et al, 1999;Ma et al, 2003), and by markedly defective axonal growth (Eng et al, 2001).…”

Brn-3a/POU4F1 interacts with and differentially affects p73-mediated transcription

“…20 These neurons are rescued during embryogenesis by the loss of bax as demonstrated in Brn-3a/Bax double KO. 3,4 Thus, the ability of Brn-3a to antagonize transactivation of Bax by p73 is likely to play an important role in neuronal survival during development. It is also possible that p73 might regulate the transition of undifferentiated Brn-3a expressing NCC to differentiated neurons.…”

“…1,2 It is essential for the survival and normal differentiation of these neurons during development since loss of Brn-3a in knockout (KO) mice results in extensive apoptosis of somato-sensory neurons with subsequent death of mutants mice by postnatal day 1 (P1). 3,4 Brn-3a enhances the survival of neuronal cultures prepared from dorsal root ganglia and trigeminal ganglia following neurotrophic withdrawal, whereas loss of Brn-3a results in apoptosis even in the presence of neurotrophic factors. 5,6 Increasing Brn-3a also enhances neuronal survival following nerve injury, for example in sciatic nerve crush.…”