The haplotypes of Y chromosome (paternally inherited) and mtDNA (maternally inherited) were analyzed in representatives of six Jewish communities (Ashkenazic, North African, Near Eastern, Yemenite, Minor Asian/Balkanian, and Ethiopian). For both elements, the Ethiopian community has a mixture of typically African and typically Caucasian haplotypes and is significantly different from all others. The other communities, whose haplotypes are mostly Caucasian, are more closely related; significant differences that were found among some of them possibly indicate the effects of admixture with neighboring communities of non-Jews. The different contribution of the Y chromosome and mtDNA haplotypes to the significant differences among the communities can be explained by unequal involvement of males and females in the different admixtures. In all communities, except the Ethiopians, the level of diversity (h) for Y chromosome haplotypes is higher than that for mtDNA haplotypes, suggesting that in each community the people who become parents include more males than females. An opposite proportion (more females than males) is found among the Ethiopians.

PC12 cells, derived from a rat pheochromocytoma, have been extensively used as a model of neuronal differentiation (1), because the cells acquire the phenotype of sympathetic neurons and stop dividing in response to nerve growth factor (NGF) 1 (2).In PC12 cells, NGF interacts with two distinct plasma membrane receptor proteins: p75 NGFR , a cysteine-rich glycoprotein having a relatively low affinity for NGF (3), and p140 trk , a receptor tyrosine kinase activated by NGF, which binds NGF with high affinity and mediates many of the biological activities of this neurotrophin (4). The binding of NGF to the p140 trk receptor stimulates rapid tyrosine autophosphorylation of the receptor and activation of several signal-transducing proteins (4). Activated p140 trk receptors bind to and tyrosine phosphorylate the signaling substrates phospholipase C␥1, phosphatidylinositol-3 kinase, and Src homologous collagen protein (4), resulting in their activation. The latter stimulates Ras activity which subsequently activates a series of serine/threonine kinases including B-Raf, myelin basic protein kinase kinase, the Erks, and p90 rsk (4). This Ras-Erk pathway plays a major role in the activation of transcriptional events by NGF and in NGFinduced neuronal differentiation (5), as illustrated by inhibition of NGF actions upon expression of dominant-negative HaRas (Asn-17) proteins (6, 7). In addition a role for pp60 c-src in NGF actions has been suggested (5) by experiments involving the expression of a dominant-interfering kinase-inactive Src (8).PC12 cells also express plasma membrane receptors for epidermal growth factor (EGF) (9, 10), a mild mitogen for these cells (9). PC12 cells treated with NGF exhibit an attenuated response to EGF (9) because EGF receptors are down-regulated (9, 11). The cellular mechanisms that mediate NGF-induced EGF receptor down-regulation are unknown and represent an interesting question in neuronal development. The existence of functional receptors for both NGF and EGF on PC12 cells and the recent advances in understanding the signaling pathways activated by these receptors make these cells a useful model for the study of cross-regulation between NGF and EGF receptors during differentiation.In this study, we have used a number of PC12 variant cell lines with different levels of p140 trk (12, 13) and EGF receptor expression and dominant-negative Ras (7,14,15) or Src (5,6,8) PC12 transfectants in an attempt to elucidate the molecular mechanisms of the receptor cross-talk required by NGF to down-regulate EGF receptors. Our findings implicate the involvement of p140 trk -, Ras-, and Src-dependent signaling pathways in NGF-induced down-regulation of EGF receptors while * The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. ‡ Permanent address:

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A novel neuronal model (PC12EN cells), obtained by somatic hybridization of rat adrenal medullary pheochromocytoma (PC12) and bovine adrenal medullary endothelial (BAME) cells, was developed. PC12EN cells maintained numerous neuronal characteristics: they expressed neuronal glycolipid conjugates, synthesized and secreted catecholamines, and responded to differentiative agents with neurite outgrowth. PC12EN lacked receptors for EGF and both the p75 and trk NGF receptors, while FGF receptor expression was maintained. Staurosporine (5-50 nM), but not other members of the K252a family of protein kinase inhibitors, rapidly induced neurite outgrowth in PC12EN, as also found in the parental PC12 cells, but not in BAME cells. Similarly, both acidic and basic FGF (1-100 ng/ml) were neurotropic in PC12EN. In contrast to the mechanism by which FGF promoted neurite outgrowth in PC12EN, the neurotropic effect of staurosporine did not involve activation of established signalling pathways, such as tyrosine phosphorylation of erk (ras pathway) or SNT (a specific target of neuronal differentiation). In addition, staurosporine induced the tyrosine phosphorylation of the focal adhesion kinase p125FAK. However, since the latter effect was also observed with other protein kinase inhibitors of the K252a family, which induced PC12EN cells flattening but no neurite extension, we propose that FAK tyrosine phosphorylation may be related to ubiquitous changes in cell shape. We anticipate that PC12EN neuronal hybrids will become useful models in neuroscience research for evaluating unique cellular signalling mechanisms of novel neurotropic compounds.