The protein tyrosine kinase PYK2, which is highly expressed in the central nervous system, is rapidly phosphorylated on tyrosine residues in response to various stimuli that elevate the intracellular calcium concentration, as well as by protein kinase C activation. Activation of PYK2 leads to modulation of ion channel function and activation of the MAP kinase signalling pathway. PYK2 activation may provide a mechanism for a variety of short- and long-term calcium-dependent signalling events in the nervous system.

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Rapid conduction in myelinated axons depends on the generation of specialized subcellular domains to which different sets of ion channels are localized. Here, we describe the identification of Caspr2, a mammalian homolog of Drosophila Neurexin IV (Nrx-IV), and show that this neurexin-like protein and the closely related molecule Caspr/Paranodin demarcate distinct subdomains in myelinated axons. While contactin-associated protein (Caspr) is present at the paranodal junctions, Caspr2 is precisely colocalized with Shaker-like K+ channels in the juxtaparanodal region. We further show that Caspr2 specifically associates with Kv1.1, Kv1.2, and their Kvbeta2 subunit. This association involves the C-terminal sequence of Caspr2, which contains a putative PDZ binding site. These results suggest a role for Caspr family members in the local differentiation of the axon into distinct functional subdomains.

The Caribbean basin is home to some of the most complex interactions in recent history among previously diverged human populations. Here, we investigate the population genetic history of this region by characterizing patterns of genome-wide variation among 330 individuals from three of the Greater Antilles (Cuba, Puerto Rico, Hispaniola), two mainland (Honduras, Colombia), and three Native South American (Yukpa, Bari, and Warao) populations. We combine these data with a unique database of genomic variation in over 3,000 individuals from diverse European, African, and Native American populations. We use local ancestry inference and tract length distributions to test different demographic scenarios for the pre- and post-colonial history of the region. We develop a novel ancestry-specific PCA (ASPCA) method to reconstruct the sub-continental origin of Native American, European, and African haplotypes from admixed genomes. We find that the most likely source of the indigenous ancestry in Caribbean islanders is a Native South American component shared among inland Amazonian tribes, Central America, and the Yucatan peninsula, suggesting extensive gene flow across the Caribbean in pre-Columbian times. We find evidence of two pulses of African migration. The first pulse—which today is reflected by shorter, older ancestry tracts—consists of a genetic component more similar to coastal West African regions involved in early stages of the trans-Atlantic slave trade. The second pulse—reflected by longer, younger tracts—is more similar to present-day West-Central African populations, supporting historical records of later transatlantic deportation. Surprisingly, we also identify a Latino-specific European component that has significantly diverged from its parental Iberian source populations, presumably as a result of small European founder population size. We demonstrate that the ancestral components in admixed genomes can be traced back to distinct sub-continental source populations with far greater resolution than previously thought, even when limited pre-Columbian Caribbean haplotypes have survived.

Barnea et al., 1994;Maurel et al., 1994). It has been expressed on the surface of glial cells binds to the shown that the expression of RPTPβ is restricted to the glycosylphosphatidylinositol (GPI)-anchored recogninervous system. RPTPβ is expressed in cells that have been tion molecule contactin on neuronal cells leading to implicated in neuronal migration and axonal guidance, neurite outgrowth. We describe the cloning of a novel including glial precursors, radial glia and astrocytes (Rauch contactin-associated transmembrane receptor (p190 Canoll et al., 1993). RPTPβ also bears the Caspr) containing a mosaic of domains implicated in HNK-1 carbohydrate epitope that is found in several protein-protein interactions. The extracellular domain neuronal adhesion molecules and was implicated in cell of Caspr contains a neurophilin/coagulation factor recognition and axonal guidance (Rauch et al., 1991). In homology domain, a region related to fibrinogen β/γ, Drosophila, the analogous HRP carbohydrate epitope was epidermal growth factor-like repeats, neurexin motifs found in neural recognition molecules as well as in as well as unique PGY repeats found in a molluscan receptor protein tyrosine phosphatases that are expressed adhesive protein. The cytoplasmic domain of Caspr in the developing nervous system (Desai et al., 1994). It contains a proline-rich sequence capable of binding to was demonstrated recently that loss-of-function mutations a subclass of SH3 domains of signaling molecules.in Drosophila RPTPs result in erroneous pathfinding Caspr and contactin exist as a complex in rat brain of certain motor axons (Desai et al., 1996; Krueger and are bound to each other by means of lateral (cis) et al., 1996). interactions in the plasma membrane. We proposeIn our attempts to identify specific ligands of RPTPβ, that Caspr may function as a signaling component we used soluble, recombinant CAH or FNIII domains of of contactin, enabling recruitment and activation of this receptor phosphatase as specific reagents for the intracellular signaling pathways in neurons. The bindidentification of cellular proteins that bind to RPTPβ. We ing of RPTPβ to the contactin-Caspr complex could have demonstrated that the FNIII repeat binds specifically provide a mechanism for cell-cell communication to glial cells while the CAH domain of RPTPβ binds to between glial cells and neurons during development.neurons or cells of neuronal origin .