Biomedical subjects

Manzoor A Bhat

Publications and source records attributed to Manzoor A Bhat.

8 recordsLinked to original sources

PubMed2006

In vivo inactivation of pRb, p107 and p130 in murine neuroprogenitor cells leads to major CNS developmental defects and high seizure rates.

Nestin-positive cells were targeted for pRb, p107 and p130 (pRb(f)) inactivation by expression of T(121), a truncated SV40 large T antigen that selectively binds to and inactivates pRb(f). Cre expression was initiated under GFAP control, resulting in T(121) expression restricted to neuroprogenitor cells beginning at embryonic day 11.5 (E11.5). Bi-transgenic embryos showed aberrant central nervous system (CNS) cell proliferation and apoptosis by E13.5. Defects in cortical development were evident with primary effects resulting in depletion of neural progenitors and aberrant cellular migration. Consequently, juvenile and adult brain morphology was reproducibly abnormal, including disorganization of neocortical, hippocampal and cerebellar regions. These aberrations resulted in behavioral phenotypes, including ataxia and seizures. The data indicate that inactivation of pRb(f) in radial glial cells, a population of neuroprogenitor cells, leads to specific disruptions in CNS patterning. The neuroprogenitor-restricted transgene expression provides a model in which to explore both developmental mechanisms and functional neurological outcomes.

Animals↗

PubMed2006

Axonal ensheathment and septate junction formation in the peripheral nervous system of Drosophila.

Axonal insulation is critical for efficient action potential propagation and normal functioning of the nervous system. In Drosophila, the underlying basis of nerve ensheathment is the axonal insulation by glial cells and the establishment of septate junctions (SJs) between glial cell membranes. However, the details of the cellular and molecular mechanisms underlying axonal insulation and SJ formation are still obscure. Here, we report the characterization of axonal insulation in the Drosophila peripheral nervous system (PNS). Targeted expression of tau-green fluorescent protein in the glial cells and ultrastructural analysis of the peripheral nerves allowed us to visualize the glial ensheathment of axons. We show that individual or a group of axons are ensheathed by inner glial processes, which in turn are ensheathed by the outer perineurial glial cells. SJs are formed between the inner and outer glial membranes. We also show that Neurexin IV, Contactin, and Neuroglian are coexpressed in the peripheral glial membranes and that these proteins exist as a complex in the Drosophila nervous system. Mutations in neurexin IV, contactin, and neuroglian result in the disruption of blood-nerve barrier function in the PNS, and ultrastructural analyses of the mutant embryonic peripheral nerves show loss of glial SJs. Interestingly, the murine homologs of Neurexin IV, Contactin, and Neuroglian are expressed at the paranodal SJs and play a key role in axon-glial interactions of myelinated axons. Together, our data suggest that the molecular machinery underlying axonal insulation and axon-glial interactions may be conserved across species.

Animals↗

PubMed2006

Disruption of axo-glial junctions causes cytoskeletal disorganization and degeneration of Purkinje neuron axons.

Axo-glial junctions (AGJs) play a critical role in the organization and maintenance of molecular domains in myelinated axons. Neurexin IV/Caspr1/paranodin (NCP1) is an important player in the formation of AGJs because it recruits a paranodal complex implicated in the tethering of glial proteins to the axonal membrane and cytoskeleton. Mice deficient in either the axonal protein NCP1 or the glial ceramide galactosyltransferase (CGT) display disruptions in AGJs and severe ataxia. In this article, we correlate these two phenotypes and show that both NCP1 and CGT mutants develop large swellings accompanied by cytoskeletal disorganization and degeneration in the axons of cerebellar Purkinje neurons. We also show that alphaII spectrin is part of the paranodal complex and that, although not properly targeted, this complex is still formed in CGT mutants. Together, these findings establish a physiologically relevant link between AGJs and axonal cytoskeleton and raise the possibility that some neurodegenerative disorders arise from disruption of the AGJs.

Animals↗

PubMed2006

Organization and function of septate junctions: an evolutionary perspective.

In most cell types, distinct forms of intercellular junctions have been visualized at the ultrastructural level. Among these, the septate junctions are thought to seal the neighboring cells and thus to function as the paracellular barriers. The most extensively studied form of septate junctions, referred to as the pleated septate junctions, is ultrastructurally distinct with an electron-dense ladder-like arrangement of transverse septa present in invertebrates as well as vertebrates. In invertebrates, such as the fruit fly Drosophila melanogaster, septate junctions are present in all ectodermally derived epithelia, imaginal discs, and the nervous system. In vertebrates, septate junctions are present in the myelinated nerves at the paranodal interface between the myelin loops and the axonal membrane. In this review, we present an evolutionary perspective of septate junctions, especially their initial identification across phyla, and discuss many common features of their morphology, molecular organization, and functional similarities in invertebrates and vertebrates.

Animals↗

PubMed2004

Drosophila contactin, a homolog of vertebrate contactin, is required for septate junction organization and paracellular barrier function.

Septate junctions (SJs) in epithelial and neuronal cells play an important role in the formation and maintenance of charge and size selective barriers. They form the basis for the ensheathment of nerve fibers in Drosophila and for the attachment of myelin loops to axonal surface in vertebrates. The cell-adhesion molecules NRX IV/Caspr/Paranodin (NCP1), contactin and Neurofascin-155 (NF-155) are all present at the vertebrate axo-glial SJs. Mutational analyses have shown that vertebrate NCP1 and its Drosophila homolog, Neurexin IV (NRX IV) are required for the formation of SJs. In this study, we report the genetic, molecular and biochemical characterization of the Drosophila homolog of vertebrate contactin, CONT. Ultrastructural and dye-exclusion analyses of Cont mutant embryos show that CONT is required for organization of SJs and paracellular barrier function. We show that CONT, Neuroglian (NRG) (Drosophila homolog of NF-155) and NRX IV are interdependent for their SJ localization and these proteins form a tripartite complex. Hence, our data provide evidence that the organization of SJs is dependent on the interactions between these highly conserved cell-adhesion molecules.

Animals↗

PubMed2003

Molecular organization of axo-glial junctions.

Axo-glial interactions are required for the organization of highly specialized molecular domains in myelinated axons. The molecular composition of these domains includes cell adhesion molecules, ion channels and cytoskeletal proteins. Recent genetic and molecular studies provide new insights into how these macromolecular complexes are assembled and organized into functional domains, and how the loss of individual components affects domain organization and function. More importantly, the key molecular components identified at the vertebrate axo-glial septate junctions are also present at the Drosophila septate junctions. In addition, new roles for axo-glial paranodal septate junctions have emerged, which suggest that the paranodal region may act as an ionic barrier and a molecular fence in myelinated axons.

Animals↗

PubMed2003

Skin cancers in Western Saudi Arabia.

OBJECTIVE: A retrospective analysis of skin cancers in a major referral centre in Taif region, Kingdom of Saudi Arabia, (KSA). METHODS: The case records of all malignant skin cancers diagnosed during a 10 year period, from 1992 through to 2001 were taken for the study. The clinical and histopathological details were noted. These were compared to reports from the rest of KSA and other countries. RESULTS: One hundred and four cases of malignant skin lesions including primary and metastatic tumors were seen. The majority were Saudis. The male to female ratio was 2.25:1. Most of the patients were over the age of 60 years. Basal cell carcinoma was the most frequent (51%) followed by squamous cell carcinoma (26%) and malignant melanoma (12.5%). Other rare primary tumors were those arising from the skin appendages, dermatofibrosarcoma protuberans and Kaposi's sarcoma. Metastatic skin lesions were seen in 5; in one it resulted from a surgical procedure and in the others the primary site could not be determined. CONCLUSION: The number of patients seen in this report is not high indicating that protective factors like clothing and skin type of the individual played a protective role. However, we feel that more studies should be encouraged in other regions along with the creation of a registry within each area to monitor the information regarding skin cancers. This could then be incorporated in health education programmes to be imparted to the public.

Adult↗

PubMed2002

Drosophila Crumbs is a positional cue in photoreceptor adherens junctions and rhabdomeres.

Drosophila Crumbs (Crb) is required for apical-basal polarity and is an apical determinant in embryonic epithelia. Here, we describe properties of Crb that control the position and integrity of the photoreceptor adherens junction and photosensitive organ, or rhabdomere. In contrast to normal photoreceptor adherens junctions and rhabdomeres, which span the depth of the retina, adherens junctions and rhabdomeres of Crb-deficient photoreceptors initially accumulate at the top of the retina and fail to maintain their integrity as they stretch to the retinal floor. We show that Crb controls localization of the adherens junction through its intracellular domain containing a putative binding site for a protein 4.1 superfamily protein (FERM). Although loss of Crb or overexpression of the FERM binding domain causes mislocalization of adherens junctions, they do not result in a significant loss of photoreceptor polarity. Mutations in CRB1, a human homologue of crb, are associated with photoreceptor degeneration in retinitis pigmentosa 12 (RP12) and Leber congenital amaurosis (LCA). The intracellular domain of CRB1 behaves similarly to its Drosophila counterpart when overexpressed in the fly eye. Our studies may provide clues for mechanisms of photoreceptor degeneration in RP12 and LCA.

Adherens Junctions↗