Following the positional cloning of PDS, the gene mutated in the deafness/goitre disorder Pendred syndrome (PS), numerous studies have focused on defining the role of PDS in deafness and PS as well as elucidating the function of the PDS-encoded protein (pendrin). To facilitate these efforts and to provide a system for more detailed study of the inner-ear defects that occur in the absence of pendrin, we have generated a Pds-knockout mouse. Pds(-/-) mice are completely deaf and also display signs of vestibular dysfunction. The inner ears of these mice appear to develop normally until embryonic day 15, after which time severe endolymphatic dilatation occurs, reminiscent of that seen radiologically in deaf individuals with PDS mutations. Additionally, in the second postnatal week, severe degeneration of sensory cells and malformation of otoconia and otoconial membranes occur, as revealed by scanning electron and fluorescence confocal microscopy. The ultrastructural defects seen in the Pds(-/-) mice provide important clues about the mechanisms responsible for the inner-ear pathology associated with PDS mutations.

-/-inner ears. More severe mutant phenotypes include absence of the anterior and posterior semicircular canals, and a malformed saccule and cochlear duct. However, formation of the lateral semicircular canal and its ampulla is usually unaffected. These inner ear phenotypes are remarkably similar to those reported in kreisler mice, which have inner ear defects attributed to defects in the hindbrain. Based on gene expression analyses, we propose that activation of Gbx2 expression within the inner ear is an important pathway whereby signals from the hindbrain regulate inner ear development. In addition, our results suggest that Gbx2 normally promotes dorsal fates such as the endolymphatic duct and semicircular canals by positively regulating genes such as Wnt2b and Dlx5. However, Gbx2 promotes ventral fates such as the saccule and cochlear duct, possibly by restricting Otx2 expression.

Synechococcus elongatus PCC 7942 is a paradigmatic model organism for nitrogen regulation in cyanobacteria. Expression of genes involved in nitrogen assimilation is positively regulated by the 2-oxoglutarate receptor and global transcriptional regulator NtcA. Maximal activation requires the subsequent binding of the co-activator PipX. PII, a protein found in all three domains of life as an integrator of signals of the nitrogen and carbon balance, binds to PipX to counteract NtcA activity at low 2-oxoglutarate levels. PII-PipX complexes can also bind to the transcriptional regulator PlmA, whose regulon remains unknown. Here we expand the nitrogen regulatory network to PipY, encoded by the bicistronic operon pipXY in S. elongatus. Work with PipY, the cyanobacterial member of the widespread family of COG0325 proteins, confirms the conserved roles in vitamin B6 and amino/keto acid homeostasis and reveals new PLP-related phenotypes, including sensitivity to antibiotics targeting essential PLP-holoenzymes or synthetic lethality with cysK. In addition, the related phenotypes of pipY and pipX mutants are consistent with genetic interactions in the contexts of survival to PLP-targeting antibiotics and transcriptional regulation. We also showed that PipY overexpression increased the length of S. elongatus cells. Taken together, our results support a universal regulatory role for COG0325 proteins, paving the way to a better understanding of these proteins and of their connections with other biological processes.

The mammalian cochlea is sophisticated in its function and highly organized in its structure. Although the anatomy of this sense organ has been well documented, the molecular mechanisms underlying its development have remained elusive. Information generated from mutant and knockout mice in recent years has increased our understanding of cochlear development and physiology. This article discusses factors important for the development of the inner ear and summarizes cochlear phenotypes of mutant and knockout mice, particularly Otx and Otx2. We also present data on gross development of the mouse cochlea.T he mammalian cochlea, the end organ of auditory function, is a truly remarkable structure. Its uniquely coiled shape, diversity of cell types, and intricate architecture are unmatched by any other organs in the body. The sensory component of the cochlea, the organ of Corti, consists of both sensory hair cells and supporting cells, and it spirals like a ribbon down the cochlear duct. The cochlea is tonotopically mapped so that the hair cells at each location along the cochlea are most sensitive to a particular frequency (for review, see ref. 1). Multiple structural features of the hair cells are organized in a gradient along the cochlea that could contribute to the differential frequency selectivity of the hair cells (for review, see ref.2). For example, hair cells in the base of the cochlea have shorter cell bodies and their stereocilia are shorter and more abundant than those of hair cells in the apex. In addition, the width of the basilar membrane and the mass of the tectorial membrane also increase toward the apex of the cochlea. These overall structural gradients along the cochlea are largely conserved among different species but vary depending on the range of absolute frequencies detected and the most sensitive frequency range of an individual species. Little is known about the molecular mechanisms that establish the fine structural patterning of the cochlea or that underlie the tonotopic organization of the organ. Likewise, little is known about what makes a cochlea coil and what dictates the variation in the number of coils among different species (3). Recent gene targeting approaches in mice have provided insights by identifying a number of genes important for the shaping of the cochlea at both the gross and fine structural levels. Here, we summarize data from mutant and knockout mice with cochlear defects and highlight several features of the gross development of the cochlea that may pertain to its mature functions. Gross Development of the CochleaThe mouse inner ear can be roughly divided into a dorsal vestibular and a ventral saccular and cochlear region. The cochlea develops from the ventral portion of the rudimentary otocyst. Fig. 1 illustrates a series of developing inner ears in which the lumen has been filled with a latex paint solution to reveal its gross anatomy. At 10.75 dpc (days postcoitium), the cochlear anlage becomes evident, and it first extends ventromedially and then anteriorly. As a res...