The Sound of Silence: Mouse Models for Hearing Loss

Sensorineural hearing loss is one of the most common disabilities in humans. It is estimated that about 278 million people worldwide have slight to extreme hearing loss in both ears, which results in an economic loss for the country and personal loss for the individual. It is thus critical to have a deeper understanding of the causes for hearing loss to better manage and treat the affected individuals. The mouse serves as an excellent model to study and recapitulate some of these phenotypes, identify new genes which cause deafness, and to study their roles in vivo and in detail. Mutant mice have been instrumental in elucidating the function and mechanisms of the inner ear. The development and morphogenesis of the inner ear from an ectodermal layer into distinct auditory and vestibular components depends on well-coordinated gene expression and well-orchestrated signaling cascades within the otic vesicle and interactions with surrounding layers of tissues. Any disruption in these pathways can lead to hearing impairment. This review takes a look at some of the genes and their corresponding mice mutants that have shed light on the mechanism governing hearing impairment (HI) in humans

Regulatory Functions of Pax1 and Pax9 in Mammalian Cells

Pax1 and Pax9 are paired-box transcription factors, which play vital roles in axial skeletogenesis, thymus organogenesis, palatogenesis and odontogenesis among others. The importance of these closely related transcription factors can be perceived from the various human anomalies associated with their disruption. Vertebral column abnormalities such as kyphoscoliosis, seen in Jarcho-Levine and Klippel-Feil syndromes, secondary cleft palate, oligodontia/ hypodontia (missing teeth) and thymus developmental defects have all been associated with mutations in PAX1 and/or PAX9. In this chapter, we describe the molecular functions of Pax1 and Pax9 in various tissues during mouse development

Disk-Planet Interaction: Triggered Formation and Migration

We present three-dimensional SPH calculations of giant planets embedded in gaseous disks. Our findings are collected into a map of parameter space, exhibiting four distinct regions: Type I migration, gap formation, triggered formation of more planets, and wholly unstable disks. For Type I migration of the planet due to secular interactions with the disk material, the migration rate depends linearly on the disk mass, and is independent of the initial planet mass. For more massive disks, the planet can disturb the disk strongly enough to trigger the collapse of gas into additional giant planets. When additional planets form, their interaction as point masses dominates the subsequent behavior of the system. This mechanism allows for the rapid formation of Jupiter-mass and higher planets. Migration due to interaction with the disk can significantly change the orbits of giant planets in gas disks.Comment: 4 pages, 3 figures, to appear in Proceedings of 14th Annual October Astrophysics Conference in Maryland, "The Search for Other Worlds

Conserved and non-conserved enhancers direct tissue specific transcription in ancient germ layer specific developmental control genes

Abstract Background Identifying DNA sequences (enhancers) that direct the precise spatial and temporal expression of developmental control genes remains a significant challenge in the annotation of vertebrate genomes. Locating these sequences, which in many cases lie at a great distance from the transcription start site, has been a major obstacle in deciphering gene regulation. Coupling of comparative genomics with functional validation to locate such regulatory elements has been a successful method in locating many such regulatory elements. But most of these studies looked either at a single gene only or the whole genome without focusing on any particular process. The pressing need is to integrate the tools of comparative genomics with knowledge of developmental biology to validate enhancers for developmental transcription factors in greater detail Results Our results show that near four different genes (nkx3.2, pax9, otx1b and foxa2) in zebrafish, only 20-30% of highly conserved DNA sequences can act as developmental enhancers irrespective of the tissue the gene expresses in. We find that some genes also have multiple conserved enhancers expressing in the same tissue at the same or different time points in development. We also located non-conserved enhancers for two of the genes (pax9 and otx1b). Our modified Bacterial artificial chromosome (BACs) studies for these 4 genes revealed that many of these enhancers work in a synergistic fashion, which cannot be captured by individual DNA constructs and are not conserved at the sequence level. Our detailed biochemical and transgenic analysis revealed Foxa1 binds to the otx1b non-conserved enhancer to direct its activity in forebrain and otic vesicle of zebrafish at 24 hpf. Conclusion Our results clearly indicate that high level of functional conservation of genes is not necessarily associated with sequence conservation of its regulatory elements. Moreover certain non conserved DNA elements might have role in gene regulation. The need is to bring together multiple approaches to bear upon individual genes to decipher all its regulatory elements.</p

Simulations of gaseous disc-embedded planet interaction

We present global three-dimensional self-gravitating smoothed particle hydrodynamics (SPH) simulations of an isothermal gaseous disc interacting with an embedded planet. Discs of varying stability are simulated with planets ranging from 10 Earth masses to 2 Jupiter masses. The SPH technique provides the large dynamic range needed to accurately capture the large-scale behaviour of the disc and the small-scale interaction of the planet with surrounding material. Most runs used 105 gas particles, giving us the spatial resolution required to observe the formation of planets. We find four regions in parameter space: low-mass planets undergo type I migration; higher-mass planets can form a gap; the gravitational instability mode of planet formation in marginally stable discs can be triggered by embedded planets; discs that are completely unstable can fragment to form many planets. The disc stability is the most important factor in determining which interaction a system will exhibit. For the stable disc cases, our migration and accretion time-scales are shorter and scale differently from previously suggeste

Time-Dependence of the Mass Accretion Rate in Cluster Cooling Flows

We analyze two time-dependent cluster cooling flow models in spherical symmetry. The first assumes that the intracluster gas resides in a static external potential, and includes the effects of optically thin radiative cooling and mass deposition. This corresponds to previous steady-state cooling flow models calculated by White & Sarazin (1987). Detailed agreement is found between steady-state models and time-dependent models at fixed times in the simulations. The mass accretion rate is found either to increase or remain nearly constant once flows reach a steady state. The time rate of change of the accretion rate is strongly sensitive to the value of the mass deposition parameter q, but only mildly sensitive to the ratio beta of gravitational binding energy to gas temperature. We show that previous scaling arguments presented by Bertschinger (1988) and White (1988) are valid only for mature cooling flows with weak mass deposition (q ~< 1). The second set of models includes the effects of a secularly deepening cluster potential and secondary infall of gas from the Hubble flow. We find that such heating effects do not prevent the flows from reaching a steady state within an initial central cooling time.Comment: 22 pages (AASTeX) with 16 EPS figures; accepted for publication in The Astrophysical Journa

Genome wide binding (ChIP-Seq) of murine Bapx1 and Sox9 proteins in vivo and in vitro

AbstractThis work pertains to GEO submission GSE36672, in vivo and in vitro genome wide binding (ChIP-Seq) of Bapx1/Nkx3.2 and Sox9 proteins. We have previously shown that data from a genome wide binding assay combined with transcriptional profiling is an insightful means to divulge the mechanisms directing cell type specification and the generation of tissues and subsequent organs [1]. Our earlier work identified the role of the DNA-binding homeodomain containing protein Bapx1/Nkx3.2 in midgestation murine embryos. Microarray analysis of EGFP-tagged cells (both wildtype and null) was integrated using ChIP-Seq analysis of Bapx1/Nkx3.2 and Sox9 DNA-binding proteins in living tissue