Lrp4 Regulates Initiation of Ureteric Budding and Is Crucial for Kidney Formation – A Mouse Model for Cenani-Lenz Syndrome

Background: Development of the kidney is initiated when the ureteric bud (UB) branches from the Wolffian duct and invades the overlying metanephric mesenchyme (MM) triggering the mesenchymal/epithelial interactions that are the basis of organ formation. Multiple signaling pathways must be integrated to ensure proper timing and location of the ureteric bud formation. Methods and Principal Findings: We have used gene targeting to create an Lrp4 null mouse line. The mutation results in early embryonic lethality with a subpenetrant phenotype of kidney agenesis. Ureteric budding is delayed with a failure to stimulate the metanephric mesenchyme in a timely manner, resulting in failure of cellular differentiation and resulting absence of kidney formation in the mouse as well as comparable malformations in humans with Cenani-Lenz syndrome. Conclusion: Lrp4 is a multi-functional receptor implicated in the regulation of several molecular pathways, including Wnt and Bmp signaling. Lrp4 2/2 mice show a delay in ureteric bud formation that results in unilateral or bilateral kidney agenesis. These data indicate that Lrp4 is a critical regulator of UB branching and lack of Lrp4 results in congenital kidne

Association of a de novo 16q copy number variant with a phenotype that overlaps with Lenz microphthalmia and Townes-Brocks syndromes

<p>Abstract</p> <p>Background</p> <p>Anophthalmia and microphthalmia are etiologically and clinically heterogeneous. Lenz microphthalmia is a syndromic form that is typically inherited in an X-linked pattern, though the causative gene mutation is unknown. Townes-Brocks syndrome manifests thumb anomalies, imperforate anus, and ear anomalies. We present a 13-year-old boy with a syndromic microphthalmia phenotype and a clinical diagnosis of Lenz microphthalmia syndrome.</p> <p>Case Presentation</p> <p>The patient was subjected to clinical and molecular evaluation, including array CGH analysis. The clinical features included left clinical anophthalmia, right microphthalmia, anteriorly placed anus with fistula, chordee, ventriculoseptal defect, patent ductus arteriosus, posteriorly rotated ears, hypotonia, growth retardation with delayed bone age, and mental retardation. The patient was found to have an approximately 5.6 Mb deletion of 16q11.2q12.1 by microarray based-comparative genomic hybridization, which includes the <it>SALL1 </it>gene, which causes Townes-Brocks syndrome.</p> <p>Conclusions</p> <p>Deletions of 16q11.2q12.2 have been reported in several individuals, although those prior reports did not note microphthalmia or anophthalmia. This region includes <it>SALL1</it>, which causes Townes-Brocks syndrome. In retrospect, this child has a number of features that can be explained by the <it>SALL1 </it>deletion, although it is not clear if the microphthalmia is a rare feature of Townes-Brocks syndrome or caused by other mechanisms. These data suggest that rare copy number changes may be a cause of syndromic microphthalmia allowing a personalized genomic medicine approach to the care of patients with these aberrations.</p

Genomic Analysis of Mouse Retinal Development

The vertebrate retina is comprised of seven major cell types that are generated in overlapping but well-defined intervals. To identify genes that might regulate retinal development, gene expression in the developing retina was profiled at multiple time points using serial analysis of gene expression (SAGE). The expression patterns of 1,051 genes that showed developmentally dynamic expression by SAGE were investigated using in situ hybridization. A molecular atlas of gene expression in the developing and mature retina was thereby constructed, along with a taxonomic classification of developmental gene expression patterns. Genes were identified that label both temporal and spatial subsets of mitotic progenitor cells. For each developing and mature major retinal cell type, genes selectively expressed in that cell type were identified. The gene expression profiles of retinal Müller glia and mitotic progenitor cells were found to be highly similar, suggesting that Müller glia might serve to produce multiple retinal cell types under the right conditions. In addition, multiple transcripts that were evolutionarily conserved that did not appear to encode open reading frames of more than 100 amino acids in length (“noncoding RNAs”) were found to be dynamically and specifically expressed in developing and mature retinal cell types. Finally, many photoreceptor-enriched genes that mapped to chromosomal intervals containing retinal disease genes were identified. These data serve as a starting point for functional investigations of the roles of these genes in retinal development and physiology

Analysis of opo cis-regulatory landscape uncovers Vsx2 requirement in early eye morphogenesis

The self-organized morphogenesis of the vertebrate optic cup entails coupling the activation of the retinal gene regulatory network to the constriction-driven infolding of the retinal epithelium. Yet the genetic mechanisms underlying this coordination remain largely unexplored. Through phylogenetic footprinting and transgenesis in zebrafish, here we examine the cis-regulatory landscape of opo, an endocytosis regulator essential for eye morphogenesis. Among the different conserved enhancers identified, we isolate a single retina-specific element (H6_10137) and show that its activity depends on binding sites for the retinal determinant Vsx2. Gain- and loss-of-function experiments and ChIP analyses reveal that Vsx2 regulates opo expression through direct binding to this retinal enhancer. Furthermore, we show that vsx2 knockdown impairs the primary optic cup folding. These data support a model by which vsx2, operating through the effector gene opo, acts as a central transcriptional node that coordinates neural retina patterning and optic cup invagination in zebrafish.info:eu-repo/semantics/publishedVersio

Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism

To ensure efficient genome duplication, cells have evolved numerous factors that promote unperturbed DNA replication and protect, repair and restart damaged forks. Here we identify downstream neighbor of SON (DONSON) as a novel fork protection factor and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a replisome component that stabilizes forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATM- and Rad3-related (ATR)-dependent signaling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity and the potentiation of chromosomal instability. Hypomorphic mutations in DONSON substantially reduce DONSON protein levels and impair fork stability in cells from patients, consistent with defective DNA replication underlying the disease phenotype. In summary, we have identified mutations in DONSON as a common cause of microcephalic dwarfism and established DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability

Spatiotemporal Distribution and Habitat Preferences of Ostracods in the Coastal Karagol Lagoon, Enez, Edirne, Turkey

Karagol Lagoon is a shallow coastal wetland in the Province of Edirne, Turkey. It is far from settlements as well as not affected by fishing or other human activities and, therefore, its biota can be considered as a source of reference data for a coastal wetland in favourable conditions. Benthic ostracod communities were studied throughout the annual cycle (every second month) at three stations in the wetland. Two euryhaline and eurythermal ostracod species were recorded: Cyprideis torosa and Loxoconcha elliptica. They were present at all three stations and in all seasonal samples, showing substantial spatial and temporal variations. Cyprideis torosa was the dominant species, while L. elliptica was a secondary species. The abundance of C. torosa and L. elliptica was positively correlated with the air temperature, water temperature and salinity but negatively correlated with the oxygen saturation. The abundance of C. torosa was also positively correlated with the pH of the water

The Ecology of The Ostracoda (Crustacea) Species Obtained From Erdek Bay (The Marmara Sea, Turkey)

The aim of this study was to determine the ecology of the Ostracoda species in the sediments collected from the Erdek Bay and to observe the relationship between ecological parameters with the number of Ostracoda species and individual numbers. Sediment and water samples have been collected seasonally from 8 stations of the study area from six different depths (0.3; 1; 5; 10; 20; 30 m). Ecological features (temperature, salinity, dissolved oxygen, mud percentage, total organic carbon, and total calcium carbonate) of 92 Ostracoda species were obtained. The abundance of recent Ostracoda species and their distributional situation according to seasonal environmental factors were evaluated. The highest number of Ostracoda species and individuals were observed between 10-30 m deep stations with the highest salinity and muddy sediments. Loxoconcha rhomboidea and Xestoleberis margaritea species showed a wide distribution in different ecological environments in the research area. Also species and individual numbers of Ostracoda showed a positive correlation with ecological parameters except temperature and dissolved oxygen

SEASONAL DISTRIBUTION OF OSTRACODA IN BANDIRMA BAY AND ERDEK BAY, SEA OF MARMARA, TURKEY

A total of 112 species of Ostracoda was identified as a result of seasonal sampling (four periods a year corresponding to the seasons) at 16 stations in Bandirma Bay and Erdek Bay (Sea of Marmara, Turkey). Fifty-five of these represent new records for the fauna of the Sea of Marmara, and 18 are new records for the Recent marine fauna of Turkey. The number of ostracode species found in Erdek Bay was generally higher than that found in Bandirma Bay, except in spring. Herein the ostracode fauna of the region is documented and its structure discussed

Diversity, spatiotemporal distribution, abundance, species composition and habitat preferences of Ostracoda in Akbük and Akdeniz coastal mesosaline lagoons (Muğla, the South Aegean Region, Turkey)

Akdeniz and Akbuk lagoons are part of a shallow coastal ecosystem of great aesthetic and ecological importance, located in Mugla Province in the southern Aegean region of Turkey. In the present study, four expeditions to collect ostracods from these lagoons were conducted in May, July, October, and November of 2008. Benthic samples were obtained monthly and several environmental factors were recorded simultaneously in situ. The ecological preferences of the ostracods were monitored, and qualitative and quantitative samples were collected from three sites in Akdeniz lagoon and two sites in Akbuk lagoon. Three ostracod taxa (Cyprideis torosa, Loxoconcha elliptica and Cytherois fischeri) were identified from the Akdeniz lagoon sampling sites and one species (Cyprideis torosa) from the Akbuk lagoon sampling sites. We present and analyze the dominance and distribution of ostracod assemblages and their relationships to environmental factors: temperature, dissolved oxygen, percentage oxygen saturation, pH, redox potential, salinity, and electrical conductivity) using classification and ordination techniques. Canonical correspondence analysis (CCA) is used to characterize the relationship between ostracods and the environmental variables. Approximately 82% of the correlation between the community composition and environmental variables was explained by the first axis of the CCA ordination for the Akdeniz lagoon. The study revealed that the distribution and population density of ostracod species depends on the physicochemical properties of the environment. The reason for this is that Cyprideis torosa and Loxoconcha elliptica are euryhaline species

Distribution, diversity and some ecological characteristics of ostracods (Crustacea: Ostracoda) in Gokceada (Imbros) Island (Northern Aegean Sea, Turkey)

The aim of this study was to determine the environmental factors affecting distribution and diversity of ostracods (Crustacea: Ostracoda) in the inland waters of the northern Aegean Sea island of Gokceada (Imbros), Turkey. Over a period of one year, sampling of ostracods was performed in order to estimate the composition, richness, and diversity of the ostracod assemblages from the Gokceada Island. A total of 18 ostracod species were identified from 28 sampling sites during the course of the study. In both winter and summer seasons, Heterocypris salina (Brady, 1868) and Cyprideis torosa (Jones, 1850) were the most abundant species. Heterocypris salina and Ilyocypris gibba (Ramdohr, 1808), were the most common species. The total number of ostracods was highest in the summer (June). During the study, the freshwater temperature varied between 10 and 29 degrees C, while salinity varied between 0.1 and 41.4%; the values of pH and dissolved oxygen ranged from 7.1 to 8.4 and 5.4 to 7.9 mg L-1, respectively. The diversity of the ostracods was calculated using the Shannon-Weaver diversity index. The highest diversity (H' = 3.427) was at macrophyte-rich sampling site 8, the lowest diversity (H' = 0) was at macrophyte-poor sites 15, 17, 19, and 22. The numbers of cosmopolitan (10 species) and widespread ostracods (2 species) were higher than those of non-cosmopolitans. A close relationship exists between distribution of ostracod species and the physicochemical features of waters and typology of water resources, considering that most of the water resources on the island are fountains and their troughs and that their waters have similar physicochemical properties