Parkinson's disease (PD) is a common neurodegenerative disorder with a lifetime incidence of approximately 2 percent. A pattern of familial aggregation has been documented for the disorder, and it was recently reported that a PD susceptibility gene in a large Italian kindred is located on the long arm of human chromosome 4. A mutation was identified in the α-synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, in the Italian kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype. This finding of a specific molecular alteration associated with PD will facilitate the detailed understanding of the pathophysiology of the disorder.

Multiple endocrine neoplasia-type 1 (MEN1) is an autosomal dominant familial cancer syndrome characterized by tumors in parathyroids, enteropancreatic endocrine tissues, and the anterior pituitary. DNA sequencing from a previously identified minimal interval on chromosome 11q13 identified several candidate genes, one of which contained 12 different frameshift, nonsense, missense, and in-frame deletion mutations in 14 probands from 15 families. The MEN1 gene contains 10 exons and encodes a ubiquitously expressed 2.8-kilobase transcript. The predicted 610-amino acid protein product, termed menin, exhibits no apparent similarities to any previously known proteins. The identification of MEN1 will enable improved understanding of the mechanism of endocrine tumorigenesis and should facilitate early diagnosis.

Lateral inhibition, mediated by Notch signaling, leads to the selection of cells that are permitted to become neurons within domains defined by proneural gene expression. Reduced lateral inhibition in zebrafish mib mutant embryos permits too many neural progenitors to differentiate as neurons. Positional cloning of mib revealed that it is a gene in the Notch pathway that encodes a RING ubiquitin ligase. Mib interacts with the intracellular domain of Delta to promote its ubiquitylation and internalization. Cell transplantation studies suggest that mib function is essential in the signaling cell for efficient activation of Notch in neighboring cells. These observations support a model for Notch activation where the Delta-Notch interaction is followed by endocytosis of Delta and transendocytosis of the Notch extracellular domain by the signaling cell. This facilitates intramembranous cleavage of the remaining Notch receptor, release of the Notch intracellular fragment, and activation of target genes in neighboring cells.

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Systemic autoinflammatory diseases are driven by abnormal activation of innate immunity1. Herein we describe a new syndrome caused by high penetrance heterozygous germline mutations in the NFκB regulatory protein TNFAIP3 (A20) in six unrelated families with early onset systemic inflammation. The syndrome resembles Behçet’s disease (BD), which is typically considered a polygenic disorder with onset in early adulthood2. A20 is a potent inhibitor of the NFκB signaling pathway3. TNFAIP3 mutant truncated proteins are likely to act by haploinsufficiency since they do not exert a dominant-negative effect in overexpression experiments. Patients’ cells show increased degradation of IκBα and nuclear translocation of NFκB p65, and increased expression of NFκB-mediated proinflammatory cytokines. A20 restricts NFκB signals via deubiquitinating (DUB) activity. In cells expressing the mutant A20 protein, there is defective removal of K63-linked ubiquitin from TRAF6, NEMO, and RIP1 after TNF stimulation. NFκB-dependent pro-inflammatory cytokines are potential therapeutic targets for these patients.

MEN1 is a tumor suppressor gene that encodes a 610 amino acid nuclear protein (menin) of previously unknown function. Using a yeast two-hybrid screen with menin as the bait, we have identified the transcription factor JunD as a direct menin-interacting partner. Menin did not interact directly with other Jun and Fos family members. The menin-JunD interaction was confirmed in vitro and in vivo. Menin repressed transcriptional activation mediated by JunD fused to the Gal4 DNA-binding domain from a Gal4 responsive reporter, or by JunD from an AP1-responsive reporter. Several naturally occurring and clustered MEN1 missense mutations disrupted menin interaction with JunD. These observations suggest that menin's tumor suppressor function involves direct binding to JunD and inhibition of JunD activated transcription.

The vertebrate organizer can induce a complete body axis when transplanted to the ventral side of a host embryo 1 by virtue of its distinct head and trunk inducing properties. Wingless/Wnt antagonists secreted by the organizer have been identified as head inducers [2][3][4] . Their ectopic expression can promote head formation, whereas ectopic activation of Wnt signalling during early gastrulation blocks head formation [5][6][7] . These observations suggest that the ability of head inducers to inhibit Wnt signalling during formation of anterior structures is what distinguishes them from trunk inducers that permit the operation of posteriorizing Wnt signals 8 . Here we describe the zebrafish headless (hdl) mutant and show that its severe head defects are due to a mutation in Tcell factor-3 (Tcf3), a member of the Tcf/Lef family 9,10 . Loss of Tcf3 function in the hdl mutant reveals that hdl represses Wnt target genes. We provide genetic evidence that a component of the Wnt signalling pathway is essential in vertebrate head formation and patterning.The hdl mutant was isolated as part of a screen for ethyl nitrosourea (ENU)-induced mutations that disrupt early neurogenesis in zebrafish 11 . Mutant embryos obtained from hdl heterozygous parents, however, display a weak phenotype and are characterized by a slight reduction in eye size. Their weak phenotype allowed a subset of homozygous hdl fish to be grown to adulthood. Here, hdl mutants refers to maternally and zygotically homozygous mutant embryos. Our examination of hdl mutants with the early neuronal marker, huC 12 , revealed an aberrant pattern of trigeminal neurons (Fig. 1a, b). The mutation, however, derives its name -headless -from the head defect in embryos that is characterized by complete loss of eyes, forebrain and part of the midbrain (Fig. 1c, d, e). Analysis of the head skeleton reveals cranial-specific defects (Fig. 1f, g); the pharyngeal arches appear relatively unaffected (Fig. 1h, i Hesx1, normally expressed in the anterior neural plate (Fig. 2m), is almost absent in mutants (Fig. 2s). Mutational analysis has shown that Hesx1 is required for normal forebrain development in mice and humans 13 . Transcripts of six3, another anterior brain marker 14 , are also reduced in the anterior neural plate, but its expression in the underlying prechordal plate is not changed (Fig. 2n, t). This suggests that the hdl phenotype is not related to loss of the underlying prechordal plate. Expression of rx3, a marker for the presumptive retina and ventral forebrain, is also strongly reduced in mutants (Fig. 2o, u). Mouse embryos carrying a null allele of the Rx gene have severe defects in eye and forebrain formation 15 . The reduction in expression of these anterior neural-specific genes is accompanied by a rostral expansion of midbrain-hindbrain boundary (MHB) genes such as pax2 (Fig. 2p, v) and engrailed2 (eng2) (Fig. 2q, w) but not krox20 (krx20), expressed in rhombomeres 3 and 5 (Fig. 2w).To investigate how early changes in the vertebrate organizer contri...

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant cancer syndrome, characterized primarily by multiple tumors in the parathyroid glands, endocrine pancreas, and anterior pituitary. Other tumors, including gastrinoma, carcinoid, adrenal cortical tumors, angiofibroma, collagenoma, and lipoma, also occur in some patients. Individuals with MEN1 almost always have loss-of-function mutations in the MEN1 gene on chromosome 11, and endocrine tumors arising in these patients usually show somatic loss of the remaining wild-type allele. To examine the role of MEN1 in tumor formation, a mouse model was generated through homologous recombination of the mouse homolog Men1. Homozygous mice die in utero at embryonic days 11.5-12.5, whereas heterozygous mice develop features remarkably similar to those of the human disorder. As early as 9 months, pancreatic islets show a range of lesions from hyperplasia to insulin-producing islet cell tumors, and parathyroid adenomas are also frequently observed. Larger, more numerous tumors involving pancreatic islets, parathyroids, thyroid, adrenal cortex, and pituitary are seen by 16 months. All of the tumors tested to date show loss of the wild-type Men1 allele, further supporting its role as a tumor suppressor gene.M ultiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant cancer syndrome characterized by multiple tumors of the parathyroid, endocrine pancreas, and the anterior pituitary. Additional tumors have been associated with MEN1, including foregut carcinoid, adrenal cortical tumors, angiofibroma, collagenoma, and lipoma (1, 2). Linkage studies in affected families mapped the MEN1 locus to chromosome 11q13 (3), and the responsible gene, MEN1, was identified by positional cloning in 1997 (4). Germline mutations in MEN1 have been identified in almost all MEN1 kindreds (5-7), and somatic mutations in MEN1 have been reported in sporadic parathyroid adenomas, pituitary tumors, insulinomas, gastrinomas, and lung carcinoids (8 -12). Over 70% of germline mutations are nonsense and frameshifts, predicting truncation or absence of the resulting protein.Missense mutations and in-frame deletions account for the remaining 30% of the almost 250 unique mutations identified to date. Hence, MEN1 appears to be a classic tumor suppressor gene with tumors in affected patients showing somatic loss of the wild-type allele.The MEN1 gene consists of 10 exons (the first of which is untranslated), spanning 7.2 kb of genomic sequence and encoding a protein of 610 amino acids. The protein product, menin, does not reveal homologies to any other known proteins or possess notable motifs from which the putative function of the protein could be deduced. Menin RNA and protein apparently are expressed in all tissues (13), leaving unexplained the basis for endocrine predominance of neoplasia. Menin is found in the nucleus (14) and binds to the AP1 transcription factor JunD (15). This finding suggests a role in transcriptional regulation, although a detailed model for menin tumor suppression ...