Mutation of the LUNATIC FRINGE Gene in Humans Causes Spondylocostal Dysostosis with a Severe Vertebral Phenotype

The spondylocostal dysostoses (SCDs) are a heterogeneous group of vertebral malsegmentation disorders that arise during embryonic development by a disruption of somitogenesis. Previously, we had identified two genes that cause a subset of autosomal recessive forms of this disease: DLL3 (SCD1) and MESP2 (SCD2). These genes are important components of the Notch signaling pathway, which has multiple roles in development and disease. Here, we have used a candidate-gene approach to identify a mutation in a third Notch pathway gene, LUNATIC FRINGE (LFNG), in a family with autosomal recessive SCD. LFNG encodes a glycosyltransferase that modifies the Notch family of cell-surface receptors, a key step in the regulation of this signaling pathway. A missense mutation was identified in a highly conserved phenylalanine close to the active site of the enzyme. Functional analysis revealed that the mutant LFNG was not localized to the correct compartment of the cell, was unable to modulate Notch signaling in a cell-based assay, and was enzymatically inactive. This represents the first known mutation in the human LFNG gene and reinforces the hypothesis that proper regulation of the Notch signaling pathway is an absolute requirement for the correct patterning of the axial skeleton

Cross-talk between tight and anchoring junctions-lesson from the testis

Spermatogenesis takes place in the seminiferous tubules in adult testes such as rats, in which developing germ cells must traverse the seminiferous epithelium while spermatogonia (2n, diploid) undergo mitotic and meiotic divisions, and differentiate into elongated spermatids (1n, haploid). It is conceivable that this event involves extensive junction restructuring particularly at the blood-testis barrier (BTB, a structure that segregates the seminiferous epithelium into the basal and the adluminal compartments) that occurs at stages VII-VIII of the seminiferous epithelial cycle. As such, cross-talk between tight (TJ) and anchoring junctions [e.g., basal ectoplasmic specialization (basal ES), adherens junction (AJ), desmosome-like junction (DJ)] at the BTB must occur to coordinate the transient opening of the BTB to facilitate preleptotene spermatocyte migration. Interestingly, while there are extensively restructuring at the BTB during the epithelial cycle, the immunological barrier function of the BTB must be maintained without disruption even transiently. Recent studies using the androgen suppression and Adjudin models have shown that anchoring junction restructuring that leads to germ cell loss from the seminiferous epithelium also promotes the production of AJ (e.g., basal ES) proteins (such as N-cadherins, catenins) at the BTB site. We postulate the testis is using a similar mechanism during spermatogenesis at stage VIII of the epithelial cycle that these induced basal ES proteins, likely form a "patch" surrounding the BTB, transiently maintain the BTB integrity while TJ is "opened", such as induced by TGF-b3 or TNFa, to facilitate preleptotene spermatocyte migration. However, in other stages of the epithelial cycle other than VII and VIII when the BTB remains "closed" (for ∼10 days), anchoring junctions (e.g., AJ, DJ, and apical ES) restructuring continues to facilitate germ cell movement. Interestingly, the mechanism(s) that governs this communication between TJ and anchoring junction (e.g., basal ES and AJ) in the testis has remained obscure until recently. Herein, we provide a critical review based on the recently available data regarding the cross-talk between TJ and anchoring junction to allow simultaneous maintenance of the BTB and germ cell movement across the seminiferous epithelium. © 2008 Landes Bioscience and Springer Science+Business Media.link_to_subscribed_fulltex