Hearing depends on extracting frequency, intensity, and temporal properties from sound to generate an auditory map for acoustical signal processing. How physiology intersects with molecular specification to fine tune the developing properties of the auditory system that enable these aspects remains unclear. We made a novel conditional deletion model that eliminates the transcription factor NEUROD1 exclusively in the ear. These mice (both sexes) develop a truncated frequency range with no neuroanatomically recognizable mapping of spiral ganglion neurons onto distinct locations in the cochlea nor a cochleotopic map presenting topographically discrete projections to the cochlear nuclei. The disorganized primary cochleotopic map alters tuning properties of the inferior colliculus units, which display abnormal frequency, intensity, and temporal sound coding. At the behavioral level, animals show alterations in the acoustic startle response, consistent with altered neuroanatomical and physiological properties. We demonstrate that absence of the primary afferent topology during embryonic development leads to dysfunctional tonotopy of the auditory system. Such effects have never been investigated in other sensory systems because of the lack of comparable single gene mutation models.SIGNIFICANCE STATEMENT All sensory systems form a topographical map of neuronal projections from peripheral sensory organs to the brain. Neuronal projections in the auditory pathway are cochleotopically organized, providing a tonotopic map of sound frequencies. Primary sensory maps typically arise by molecular cues, requiring physiological refinements. Past work has demonstrated physiologic plasticity in many senses without ever molecularly undoing the specific mapping of an entire primary sensory projection. We genetically manipulated primary auditory neurons to generate a scrambled cochleotopic projection. Eliminating tonotopic representation to auditory nuclei demonstrates the inability of physiological processes to restore a tonotopic presentation of sound in the midbrain. Our data provide the first insights into the limits of physiology-mediated brainstem plasticity during the development of the auditory system.

• MeSH
• Behavior, Animal physiology   MeSH
• Inferior Colliculi anatomy & histology   physiology   MeSH
• Spiral Ganglion cytology   physiology   MeSH
• Brain Mapping MeSH
• Mesencephalon embryology   physiology   MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Cochlear Nucleus anatomy & histology   physiology   MeSH
• Hearing physiology   MeSH
• Auditory Perception genetics   physiology   MeSH
• Pregnancy MeSH
• Basic Helix-Loop-Helix Transcription Factors genetics   physiology   MeSH
• Reflex, Startle genetics   physiology   MeSH
• Vestibule, Labyrinth anatomy & histology   physiology   MeSH
• Pitch Perception physiology   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Pregnancy MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

The aim of this paper was to summarise knowledge of IL-22 involvement in multiple sclerosis (MS) and the possible link between IL-22 and two transcription factors - AHR and c-Maf. The conclusion is that despite numerous studies, the exact role of IL-22 in the pathogenesis of MS is still unknown. The expression and function of c-Maf in MS have not been studied. It seems that the functions of c-Maf and AHR are at least partly connected with IL-22, as both directly or indirectly influence the regulation of IL-22 expression. This possible connection has never been studied in MS.

• MeSH
• Adaptor Proteins, Signal Transducing physiology   MeSH
• Interleukins physiology   MeSH
• Humans MeSH
• Receptors, Aryl Hydrocarbon physiology   MeSH
• Multiple Sclerosis etiology   MeSH
• Basic Helix-Loop-Helix Transcription Factors physiology   MeSH
• Transcription Factors physiology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Activation of the aryl hydrocarbon receptor (AhR)-mediated activity is one of key events in toxicity of polycyclic aromatic hydrocarbons (PAHs). Although various classes of AhR ligands may differentially activate human and rodent AhR, there is presently a lack of data on the human AhR-inducing relative potencies (REPs) of PAHs. Here, we focused on estimation of the AhR-mediated activities of a large set of environmental PAHs in human gene reporter AZ-AhR cell line, with an aim to develop the human AhR-based REP values with potential implications for risk assessment of PAHs. The previously identified weakly active PAHs mostly failed to activate the AhR in human cells. The order for REPs of individual PAHs in human cells largely corresponded with the available data from rodent-based experimental systems; nevertheless, we identified differences up to one order of magnitude in REP values of PAHs between human and rodent cells. Higher REP values were found in human cells for some important environmental contaminants or suspected carcinogens, such as indeno[1,2,3-cd]pyrene, benz[a]anthracene or benzo[b]fluoranthene, while lower REP values were determined for methyl-substituted PAHs. Our results also indicate that a different rate of metabolism for individual PAHs in human vs. rodent cells may affect estimation of REP values in human cell-based assay, and potentially alter toxicity of some compounds, such as benzofluoranthenes, in humans. We applied the AZ-AhR assay to evaluation of the AhR-mediated activity of complex mixtures of organic compounds associated with diesel exhaust particles, and we identified the polar compounds present in these mixtures as being particularly highly active in human cells, as compared with rodent cells. The present data suggest that differences may exist between the AhR-mediated potencies of PAHs in human and rodent cells, and that the AhR-mediated effects of polar PAH derivatives and metabolites in human cell models deserve further attention.

• MeSH
• Biological Assay methods   MeSH
• Cell Line MeSH
• Carcinogens toxicity   MeSH
• Environmental Pollutants toxicity   MeSH
• Humans MeSH
• Polycyclic Aromatic Hydrocarbons toxicity   MeSH
• Receptors, Aryl Hydrocarbon metabolism   physiology   MeSH
• Genes, Reporter MeSH
• Basic Helix-Loop-Helix Transcription Factors metabolism   physiology   MeSH
• Vehicle Emissions toxicity   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH