Unique self-sustaining circadian oscillators within the brain of Drosophila melanogaster

In Drosophila circadian rhythms persist in constant darkness (DD). The small ventral Lateral Neurons (s-LN_v) mainly control the behavioral circadian rhythm in consortium with the large ventral Lateral Neurons (l-LN_v) and dorsal Lateral Neurons (LN_d). It is believed that the molecular oscillations of clock genes are the source of this persistent behavior. Indeed the s-LN_v, LN_d, Dorsal Neurons (DN)-DN₂ and DN₃ displayed self-sustained molecular oscillations in DD both at RNA and protein levels, except the DN₂ oscillates in anti-phase. In contrast, the l-LN_v and DN₁ displayed self-sustained oscillations at the RNA level, but protein oscillations quickly dampened. Having self-sustained and dampened molecular oscillators together in the DN groups suggested that they play different roles. However, all DN groups seemed to contribute together to the light-dark (LD) behavioral rhythm. The LD entrainment of LN oscillators is achieved through Rhodopsin (RH) and Cryptochrome (CRY). CRY's expression in all DN groups implicates also its role in LD entrainment of DN, like in DN₁. However, mutations in cry and glass that did not inflict LD synchronization of the DN₂, DN₃ oscillator implicate the existence of a novel photoreceptor at least in DN₃.     

Hofbauer-Buchner eyelet affects circadian photosensitivity and coordinates TIM and PER expression in Drosophila clock neurons

Extraretinal photoreception is a common input route for light resetting signals into the circadian clock of animals. In Drosophila melanogaster, substantial circadian light inputs are mediated via the blue light photoreceptor CRYPTOCHROME (CRY) expressed in clock neurons within the brain. The current model predicts that, upon light activation, CRY interacts with the clock proteins TIMELESS (TIM) and PERIOD (PER), thereby inducing their degradation, which in turn leads to a resetting of the molecular oscillations within the circadian clock. Here the authors investigate the function of another putative extraretinal circadian photoreceptor, the Hofbauer-Buchner eyelet (H-B eyelet), located between the retina and the medulla in the fly optic lobes. Blocking synaptic transmission between the H-B eyelet and its potential target cells, the ventral circadian pacemaker neurons, impaired the flies' ability to resynchronize their behavior under jet-lag conditions in the context of nonfunctional retinal photoreception and a mutation in the CRY-encoding gene. The same manipulation also affected synchronized expression of the clock proteins TIM and PER in different subsets of the clock neurons. This shows that synaptic communication between the H-B eyelet and clock neurons contributes to synchronization of molecular and behavioral rhythms and confirms that the H-B eyelet functions as a circadian photoreceptor. Blockage of synaptic transmission from the H-B eyelet in the presence of functional compound eyes and the absence of CRY also results in increased numbers of flies that are unable to synchronize to extreme photoperiods, supplying independent proof for the role of the H-B eyelet as a circadian photoreceptor.     

Phylogeography,Population Structure,and Conservation of the Javan Gibbon (<Emphasis Type="Italic">Hylobates moloch</Emphasis>)

An understanding of phylogeography and population genetics is needed for a comprehensive long-term conservation management strategy. The Javan gibbon (Hylobates moloch), an Endangered species endemic to the island of Java, has been protected since 1924 but is threatened by ongoing habitat loss, habitat degradation, and the wildlife trade. We studied the phylogeography and population genetic structure of the Javan gibbon, to define the number of Evolutionary Significant Units (ESUs) in the species, and the population genetic structure in each ESU. We sampled 47 individuals, analyzing 35 for variation in mitochondrial DNA control region, 41 for variation in 8 nuclear DNA microsatellites, and 13 for variation in 45 nuclear DNA single nucleotide polymorphisms (SNPs). We found support for two ESUs across the species range: a western ESU, extending from Ujung Kulon to Gunung Gede–Pangrango, and a central ESU, extending from Gunung Masigit–Simpang–Tilu to Gunung Slamet. Analysis of molecular variance and population structure analysis indicate significant structuring in the western ESU between Ujung Kulon and Gunung Halimun–Salak–Gede–Pangrango, and little to moderate structure in the central ESU, underscoring the importance of conserving as many populations as possible to preserve the full array of genetic diversity in this species. Our results will inform future more comprehensive population genetic surveys and the conservation genetic management of the Javan gibbon. This study demonstrates the importance of genetics when designing conservation management strategies for endangered primates.     

Knockdown of Bardet-Biedl syndrome gene BBS9/PTHB1 leads to cilia defects

Bardet-Biedl Syndrome (BBS, MIM#209900) is a genetically heterogeneous disorder with pleiotropic phenotypes that include retinopathy, mental retardation, obesity and renal abnormalities. Of the 15 genes identified so far, seven encode core proteins that form a stable complex called BBSome, which is implicated in trafficking of proteins to cilia. Though BBS9 (also known as PTHB1) is reportedly a component of BBSome, its direct function has not yet been elucidated. Using zebrafish as a model, we show that knockdown of bbs9 with specific antisense morpholinos leads to developmental abnormalities in retina and brain including hydrocephaly that are consistent with the core phenotypes observed in syndromic ciliopathies. Knockdown of bbs9 also causes reduced number and length of cilia in Kupffer's vesicle. We also demonstrate that an orthologous human BBS9 mRNA, but not one carrying a missense mutation identified in BBS patients, can rescue the bbs9 morphant phenotype. Consistent with these findings, knockdown of Bbs9 in mouse IMCD3 cells results in the absence of cilia. Our studies suggest a key conserved role of BBS9 in biogenesis and/or function of cilia in zebrafish and mammals.     

The 2003 anatomy ceremony: a service of gratitude

In keeping with a long-standing tradition, Yale Medical and Physician Associate students gather at a ceremony each year after the completion of the anatomy course. The ceremony is a chance to reflect and to give thanks. It gives students the opportunity to articulate their gratitude to the selfless individuals who donated their bodies for the benefit of education. Many family members of the donors attend the ceremony. By reading poetry, performing musical pieces, and presenting works of art, the students and their teachers express some of the emotions and thoughts that the anatomy course has evoked. The following are some of the contributions presented at this year's ceremony.     

Biology and therapy of inherited retinal degenerative disease: insights from mouse models

Retinal neurodegeneration associated with the dysfunction or death of photoreceptors is a major cause of incurable vision loss. Tremendous progress has been made over the last two decades in discovering genes and genetic defects that lead to retinal diseases. The primary focus has now shifted to uncovering disease mechanisms and designing treatment strategies, especially inspired by the successful application of gene therapy in some forms of congenital blindness in humans. Both spontaneous and laboratory-generated mouse mutants have been valuable for providing fundamental insights into normal retinal development and for deciphering disease pathology. Here, we provide a review of mouse models of human retinal degeneration, with a primary focus on diseases affecting photoreceptor function. We also describe models associated with retinal pigment epithelium dysfunction or synaptic abnormalities. Furthermore, we highlight the crucial role of mouse models in elucidating retinal and photoreceptor biology in health and disease, and in the assessment of novel therapeutic modalities, including gene- and stem-cell-based therapies, for retinal degenerative diseases.KEY WORDS: Mouse mutants, Photoreceptor, Retinal development, Retinal disease     

Fine-Scale Genetic Structure in the United Arab Emirates Reflects Endogamous and Consanguineous Culture,Population History,and Geography

The indigenous population of the United Arab Emirates (UAE) has a unique demographic and cultural history. Its tradition of endogamy and consanguinity is expected to produce genetic homogeneity and partitioning of gene pools while population movements and intercontinental trade are likely to have contributed to genetic diversity. Emiratis and neighboring populations of the Middle East have been underrepresented in the population genetics literature with few studies covering the broader genetic history of the Arabian Peninsula. Here, we genotyped 1,198 individuals from the seven Emirates using 1.7 million markers and by employing haplotype-based algorithms and admixture analyses, we reveal the fine-scale genetic structure of the Emirati population. Shared ancestry and gene flow with neighboring populations display their unique geographic position while increased intra- versus inter-Emirati kinship and sharing of uniparental haplogroups, reflect the endogamous and consanguineous cultural traditions of the Emirates and their tribes.     

Centriole is the pivot co-ordinating dynamic signaling for cell proliferation and organization during early development in the vertebrates

Vertebrates have an elaborate and functionally segmented body. It evolves from a single cell by systematic cell proliferation but attains a complex body structure with exquisite precision. This development requires two cellular events: cell cycle and ciliogenesis. For these events, the dynamic molecular signaling is converged at the centriole. The cell cycle helps in cell proliferation and growth of the body and is a highly regulated and integrated process. Its errors cause malignancies and developmental disorders. The cells newly proliferated are organized during organogenesis. For a cellular organization, dedicated signaling hubs are developed in the cells, and most often cilia are utilized. The cilium is generated from one of the centrioles involved in cell proliferation. The developmental signaling pathways hosted in cilia are essential for the elaboration of the body plan. The cilium's compartmental seclusion is ideal for noise-free molecular signaling and is essential for the precision of the body layout. The dysfunctional centrioles and primary cilia distort the development of body layout that manifest as serious developmental disorders. Thus, centriole has a dual role in the growth and cellular organization. It organizes dynamically expressed molecules of cell cycle and ciliogenesis and plays a balancing act to generate new cells and organize them during development. A putative master molecule may regulate and co-ordinate the dynamic gene expression at the centrioles. The convergence of many critical signaling components at the centriole reiterates the idea that centriole is a major molecular workstation involved in elaborating the structural design and complexity in vertebrates.