A modifier locus on chromosome 5 contributes to L1 cell adhesion molecule X-linked hydrocephalus in mice.

Humans with L1 cell adhesion molecule (L1CAM) mutations exhibit X-linked hydrocephalus, as well as other severe neurological disorders. L1-6D mutant mice, which are homozygous for a deletion that removes the sixth immunoglobulin-like domain of L1cam, seldom display hydrocephalus on the 129/Sv background. However, the same L1-6D mutation produces severe hydrocephalus on the C57BL/6J background. To begin to understand how L1cam deficiencies result in hydrocephalus and to identify modifier loci that contribute to X-linked hydrocephalus by genetically interacting with L1cam, we conducted a genome-wide scan on F2 L1-6D mice, bred from L1-6D 129S2/SvPasCrlf and C57BL/6J mice. Linkage studies, utilizing chi-square tests and quantitative trait loci mapping techniques, were performed. Candidate modifier loci were further investigated in an extension study. Linkage was confirmed for a locus on chromosome 5, which we named L1cam hydrocephalus modifier 1 (L1hydro1), p = 4.04 X 10(-11).

Characterization of a novel primary culture system of adult zebrafish brainstem cells.

Adult zebrafish (Danio rerio) have a remarkable ability to restore function after an injury to the brain or spinal cord. The molecular and cellular mechanisms underlying this phenomenon are not fully understood. To enable investigation of these mechanisms we have developed an in vitro model system from the adult zebrafish brainstem, which can be maintained under serum-containing and serum-free conditions. While cultures are predominantly neuronal, they also contain glia and stem progenitor cells. Various stages of cellular differentiation are observed among both neuronal and non-neuronal populations. Quantitative morphological results revealed typical cellular growth over a two-week period. We argue that our novel brainstem culture model offers a powerful tool for the studies of axonal growth, neurogenesis, and regeneration in the adult zebrafish central nervous system.

Axonal regeneration after spinal cord injury in zebrafish and mammals: differences, similarities, translation.

Spinal cord injury (SCI) in mammals results in functional deficits that are mostly permanent due in part to the inability of severed axons to regenerate. Several types of growth-inhibitory molecules expressed at the injury site contribute to this regeneration failure. The responses of axons to these inhibitors vary greatly within and between organisms, reflecting axons' characteristic intrinsic propensity for regeneration. In the zebrafish (Danio rerio) many but not all axons exhibit successful regeneration after SCI. This review presents and compares the intrinsic and extrinsic determinants of axonal regeneration in the injured spinal cord in mammals and zebrafish. A better understanding of the molecules and molecular pathways underlying the remarkable individualism among neurons in mature zebrafish may support the development of therapies for SCI and their translation to the clinic.

Notch signaling patterns Drosophila mesodermal segments by regulating the bHLH transcription factor twist.

One of the first steps in embryonic mesodermal differentiation is allocation of cells to particular tissue fates. In Drosophila, this process of mesodermal subdivision requires regulation of the bHLH transcription factor Twist. During subdivision, Twist expression is modulated into stripes of low and high levels within each mesodermal segment. High Twist levels direct cells to the body wall muscle fate, whereas low levels are permissive for gut muscle and fat body fate. We show that Su(H)-mediated Notch signaling represses Twist expression during subdivision and thus plays a critical role in patterning mesodermal segments. Our work demonstrates that Notch acts as a transcriptional switch on mesodermal target genes, and it suggests that Notch/Su(H) directly regulates twist, as well as indirectly regulating twist by activating proteins that repress Twist. We propose that Notch signaling targets two distinct 'Repressors of twist' - the proteins encoded by the Enhancer of split complex [E(spl)C] and the HLH gene extra machrochaetae (emc). Hence, the patterning of Drosophila mesodermal segments relies on Notch signaling changing the activities of a network of bHLH transcriptional regulators, which, in turn, control mesodermal cell fate. Since this same cassette of Notch, Su(H) and bHLH regulators is active during vertebrate mesodermal segmentation and/or subdivision, our work suggests a conserved mechanism for Notch in early mesodermal patterning.