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Mammalian hearing requires the development of the organ of Corti, a sensory epithelium comprising unique cell types. The limited number of each of these cell types, combined with their close proximity, has prevented characterization of individual cell types and/or their developmental progression. To examine cochlear development more closely, we transcriptionally profile approximately 30,000 isolated mouse cochlear cells collected at four developmental time points. Here we report on the analysis of those cells including the identification of both known and unknown cell types. Trajectory analysis for OHCs indicates four phases of gene expression while fate mapping of progenitor cells suggests that OHCs and their surrounding supporting cells arise from a distinct (lateral) progenitor pool. Tgfβr1 is identified as being expressed in lateral progenitor cells and a Tgfβr1 antagonist inhibits OHC development. These results provide insights regarding cochlear development and demonstrate the potential value and application of this data set. How the development of the cochlear epithelium is regulated is unclear. Here, the authors use single cell RNAseq analysis to provide insight into the transcriptional changes arising during development of the murine cochlear inner and outer hair cells.

The sensory cells that are responsible for hearing include the cochlear inner hair cells (IHCs) and outer hair cells (OHCs), with the OHCs being necessary for sound sensitivity and tuning 1 . Both cell types are thought to arise from common progenitors; however, our understanding of the factors that control the fate of IHCs and OHCs remains limited. Here we identify Ikzf2 (which encodes Helios) as an essential transcription factor in mice that is required for OHC functional maturation and hearing. Helios is expressed in postnatal mouse OHCs, and in the cello mouse model a point mutation in Ikzf2 causes early-onset sensorineural hearing loss. Ikzf2 cello/cello OHCs have greatly reduced prestin-dependent electromotile activity, a hallmark of OHC functional maturation, and show reduced levels of crucial OHC-expressed genes such as Slc26a5 (which encodes prestin) and Ocm . Moreover, we show that ectopic expression of Ikzf2 in IHCs: induces the expression of OHC-specific genes; reduces the expression of canonical IHC genes; and confers electromotility to IHCs, demonstrating that Ikzf2 can partially shift the IHC transcriptome towards an OHC-like identity. Ikzf2 , which encodes the transcription factor Helios, is identified as a crucial regulator of gene expression in maturing cochlear outer hair cells, and overexpression of Ikzf2 in inner hair cells induces prestin expression and electromotility.

em>Culinary Landmarks is a definitive history and bibliography of Canadian cookbooks from the beginning, when La cuisinière bourgeoise was published in Quebec City in 1825, to the mid-twentieth century.

The transcriptional activator ATOH1 is a master regulator of the development of mechanosensory hair-cells (HCs) in the ear. We report that the ATOH1 target gene encodes a transcription factor that regulates the rate of outer HC (OHC) maturation by gene repression. Genetic deletion of during (but not after) development of the mouse cochlea caused: hearing loss; abnormal organization of mechanosensory stereocilia bundles in OHCs; abnormally low F-actin density in OHC cuticular plates; progressive loss of OHCs; and mild morphological alterations in inner HCs. RNA sequencing revealed that deletion delayed downregulation of genes expressed in immature OHCs, including the actin regulator-encoding gene , and accelerated upregulation of genes expressed in mature OHCs. knockdown restored the density of cuticular plate F-actin in mutant OHCs. Our data indicate that CASZ1 regulates transcriptional and morphological maturation of OHCs, and that CASZ1 in maturing HCs is necessary for hearing.

The sensory cells responsible for hearing include the cochlear inner hair cells (IHCs) and outer hair cells (OHCs), with OHCs being necessary for sound sensitivity and tuning. Both cell types are thought to arise from common progenitors, however our understanding of the factors that control IHC and OHC fate remains limited. Here we identify Ikzf2/helios as an essential transcription factor required for OHC functional maturation and hearing. Ikzf2/helios is expressed in postnatal mouse OHCs, and a mutation in Ikzf2 causes early-onset sensorineural hearing loss in the cello mouse model. Ikzf2cello/cello OHCs have greatly reduced prestin-dependent electromotile activity, a hallmark of OHC functional maturation, and show reduced levels of critical OHC-expressed genes such as Slc26a5/prestin and Ocm. Moreover, we show that ectopic expression of Ikzf2/helios in IHCs induces expression of OHC-specific genes, reduces canonical IHC genes, and confers electromotility to IHCs, demonstrating that Ikzf2/helios is capable of partially shifting the IHC transcriptome towards an OHC-like identity.

Notch signaling regulates both inner and middle ear morphogenesis and establishes a strict pattern of sensory cells in the organ of Corti in the mammalian cochlea. Patients with Alagille syndrome have impaired Notch signaling (~94% with JAG1 mutations) resulting in sensorineural and conductive hearing loss. Here, we investigate the function of Jag1-mediated Notch activation in cochlear patterning and signaling using the Jag1 Nodder (Jag1Ndr/Ndr) mouse model of Alagille syndrome. Jag1Ndr/Ndr mice exhibited severe vestibular and auditory deficits and a dose-dependent increase in ectopic inner hair cells and a reduction in outer hair cells. Single cell RNA sequencing of the organ of Corti demonstrated a global dysregulation of genes associated with inner ear development and deafness. Analysis of individual cell types indicated a novel role for Jag1 in repressing Notch activation in lateral supporting cells and revealed a function for Jag1 in gene regulation and development of outer hair cells. Additionally, outer hair cell-like SLC26A5 (Prestin) positive cells were present in the medial compartment and pillar cell region of Jag1Ndr/Ndr mice and exhibited location-dependent expression of the inner hair cell fate-regulator Tbx2, revisiting the potency of Tbx2 in driving inner hair cell commitment in outer hair cell-like cells in the Jag1-mutant IHC compartment. Our data reveals a novel role for Jag1 in repressing Notch activation in lateral supporting cells and highlights involvement for Notch signaling in inner versus outer hair cell specification and positioningCompeting Interest StatementThe authors have declared no competing interest.Footnotes* https://github.com/Emma-R-Andersson-Lab

Though Wittgenstein has been most often identified as opposing Platonism in his writings about mathematics, I argue that Wittgenstein’s radical contextualism about mathematics finds its most natural opponent not in Platonism, but in a variety of formalism. One of Wittgenstein’s obvious formalist targets is his colleague the mathematician G. H. Hardy. If we discard this—still influential—picture of mathematics and replace it with a more nuanced account of mathematical activity as exemplified in the metamathematical thinking of the nineteenth century mathematician Augustus De Morgan, the example of the wayward pupil takes on a different significance. Against a more complex background, the wayward pupil can be reinterpreted as representing an exemplar of mathematical discovery. I consider the example of the nineteenth century engineer Oliver Heaviside whose unconventional approach in mathematics, driven by a need to efficiently elicit results from complex formulae for the purposes of aiding his research in electrical engineering, resulted in extraordinary mathematical advances. Yet, his approach to algebraic manipulation has the aspect of a wayward pupil. The wayward pupil, who may be making an error according to our ordinary criteria of rule-following, may be initiating new and fruitful paths. This possibility is largely unexamined in the larger discussion of Wittgenstein’s remarks on following a rule, and it explains Wittgenstein’s hesitation to label the wayward pupil’s actions straightforwardly incorrect.

Bearded sprangletop (Leptochloa fusca spp. fasicularis) is a troublesome weedy species in California rice fields. Its control is chiefly dependent on the water-seeded, continuously flooded rice system and herbicides. As a result of the continuous monocrop system of rice, herbicide-resistant populations of bearded sprangletop have been selected in California rice fields. Recently, poor control with clomazone has been reported by many California rice growers. In addition, anecdotal evidence from California rice growers suggest bearded sprangletop may have adapted to the flooding pressures used in the cropping system for weed control. We hypothesized that the low clomazone efficacy observed in California populations is due to the selection of a clomazone-resistant biotype and that this resistance is the results of a non-target mechanism of resistance. We also hypothesized that bearded sprangletop populations have adapted to the standard flood used in California rice fields. Greenhouse, field and laboratory experiments were conducted to characterize putative herbicide-resistant bearded sprangletop populations from California. Greenhouse survey and dose-response experiments confirmed the presence of clomazone resistance in four bearded sprangletop populations from California. Laboratory experiments with the clomazone-resistant biotypes of bearded sprangletop indicate that metabolism of clomazone is involved in the resistance mechanism. Resistance to clomazone in these biotypes is due the oxidation of the parent molecule to less toxic metabolites within the plant. Field experiments across the Sacramento Valley indicated that failures of clomazone in the rice growing region are likely due to the later emergence of bearded sprangletop and that clomazone application are made too early in the season for effective control. These field experiments also indicated that bearded sprangletop has adapted to flooding pressures and the standard 10 cm flood is not adequate to suppress or control the weed. These results add generally to the body of knowledge of herbicide resistance in bearded sprangletop and can provide important information to growers and pest control advisors managing bearded sprangletop in California rice.