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BackgroundParkinson's disease (PD) is a neurodegenerative movement disorder affecting 1-5% of the general population for which neither effective cure nor early diagnostic tools are available that could tackle the pathology in the early phase. Here we report a multi-stage procedure to identify candidate genes likely involved in the etiopathogenesis of PD.MethodsThe study includes a discovery stage based on the analysis of whole exome data from 26 dominant late onset PD families, a validation analysis performed on 1542 independent PD patients and 706 controls from different cohorts and the assessment of polygenic variants load in the Italian cohort (394 unrelated patients and 203 controls).ResultsFamily-based approach identified 28 disrupting variants in 26 candidate genes for PD including PARK2, PINK1, DJ-1(PARK7), LRRK2, HTRA2, FBXO7, EIF4G1, DNAJC6, DNAJC13, SNCAIP, AIMP2, CHMP1A, GIPC1, HMOX2, HSPA8, IMMT, KIF21B, KIF24, MAN2C1, RHOT2, SLC25A39, SPTBN1, TMEM175, TOMM22, TVP23A and ZSCAN21. Sixteen of them have not been associated to PD before, were expressed in mesencephalon and were involved in pathways potentially deregulated in PD. Mutation analysis in independent cohorts disclosed a significant excess of highly deleterious variants in cases (p = 0.0001), supporting their role in PD. Moreover, we demonstrated that the co-inheritance of multiple rare variants (≥ 2) in the 26 genes may predict PD occurrence in about 20% of patients, both familial and sporadic cases, with high specificity (> 93%; p = 4.4 × 10- 5). Moreover, our data highlight the fact that the genetic landmarks of late onset PD does not systematically differ between sporadic and familial forms, especially in the case of small nuclear families and underline the importance of rare variants in the genetics of sporadic PD. Furthermore, patients carrying multiple rare variants showed higher risk of manifesting dyskinesia induced by levodopa treatment.ConclusionsBesides confirming the extreme genetic heterogeneity of PD, these data provide novel insights into the genetic of the disease and may be relevant for its prediction, diagnosis and treatment.

The successful segregation of germ cells from somatic lineages is vital for sexual reproduction and species survival. In the mouse, primordial germ cells (PGCs), precursors of all germ cells, are induced from the post-implantation epiblast.sup.1. Induction requires BMP4 signalling to prospective PGCs.sup.2 and the intrinsic action of PGC transcription factors.sup.3-6. However, the molecular mechanisms that connect BMP4 to induction of the PGC transcription factors that are responsible for segregating PGCs from somatic lineages are unknown. Here we show that the transcription factor OTX2 is a key regulator of these processes. Downregulation of Otx2 precedes the initiation of the PGC programme both in vitro and in vivo. Deletion of Otx2 in vitro markedly increases the efficiency of PGC-like cell differentiation and prolongs the period of PGC competence. In the absence of Otx2 activity, differentiation of PGC-like cells becomes independent of the otherwise essential cytokine signals, with germline entry initiating even in the absence of the PGC transcription factor BLIMP1. Deletion of Otx2 in vivo increases PGC numbers. These data demonstrate that OTX2 functions repressively upstream of PGC transcription factors, acting as a roadblock to limit entry of epiblast cells to the germline to a small window in space and time, thereby ensuring correct numerical segregation of germline cells from the soma.The transcription factor OTX2 ensures that germline induction is initially kept in check and only proceeds after OTX2 downregulation., Author(s): Jingchao Zhang [sup.1] , Man Zhang [sup.1] , Dario Acampora [sup.2] , Matús Vojtek [sup.1] , Detian Yuan [sup.3] , Antonio Simeone [sup.2] , Ian Chambers [sup.1] Author Affiliations:(1) [...]

The mesencephalic dopaminergic (mesDA) system controls movement and emotional behaviour, and its degeneration causes Parkinson's disease and other psychiatric disorders. Recent findings are leading to better understanding of the genetic control of generation and functioning of the mesDA system. This advancement could disclose new perspectives for therapeutic approaches of mesDA-related disorders.

Mice without the Orthopedia (Otp) gene have progressive impairment of developing hypothalamus neuroendocrine cell lineages. New data show that likely Otp and Sim1 act in parallel and are necessary to maintain Brn2 expression, which is necessary for neuronal cell lineages that secrete oxytocin, arginine vasopressin and corticotropin-releasing hormone. Sim1 is a bHLH-PAS transcription factor. It directs terminal differentiation of the supraoptic, periventricular, and anterior perventricular cells. Otp is a very conserved homeodomain-containing factor.

The murine homologs of the orthodenticle (otd) gene of Drosophila, Otx1 and Otx2, have an important role in brain morphogenesis. Analysis of Otx1 and Otx2 null mice reveals that Otx1 is required primarily for corticogenesis and sense-organ development, while Otx2 is necessary for specification and maintenance of anterior neural plate as well as for proper gastrulation. Cross-phylum recoveries of Otx1 abnormalities by Drosophila otd, and vice versa, indicate that genetic functions required in mammalian-brain development evolved in a primitive ancestor of flies and mice. Knock-in mouse models in which Otx2 was replaced with Otx1, and vice versa, provide evidence that the existence of Otx1-/- and Otx2-/- divergent phenotypes largely reflects differences in expression patterns rather than in the biochemical activity of OTX1 and OTX2. In evolutionary terms, some of these findings lead us to hypothesize a fascinating and crucial role for Otx genes that contributes to the genetic program required for the specification of the development of the vertebrate head.

Previous studies have reported that the activities of the hepatocyte growth factor (HGF) and its receptor, the Met tyrosine kinase, are mediated by specific downstream signaling pathways. Herein, replacement of the wild-type Met receptor with signaling mutants produced phenotypes characteristic of those produced by met and hgf null mutants such as embryonal death and placenta, liver and limb muscle defects. It was suggested that Met could be required to mediate a pathway in late myogenesis.

We had previously reported that in gastrulating mouse embryos retinoic acid (RA) induces morphological as well molecular alterations strictly depending on the time of administration. In particular, embryos treated with RA at the mid-late streak stage share reduction of the rostral central nervous system (CNS) and increase of the hindbrain. In the same embryos, loss of the forebrain-expressed genes, such as Emx1, Emx2, and Dlx1, and rostral ectopic expression of the Hoxb-1 gene suggest an antero-posterior (A/P) ordered repatterning of the fore-, mid-, and hindbrain regions. Several genes, such as Pax-2, Wnt-1, En-2, and En-1, are involved in the establishment of midbrain and rostral hindbrain regional identities and boundaries. We report that these genes become coordinately anteriorized only in embryos treated with RA at the late streak stage. Moreover, in the hindbrain of the same embryos, at 8.5 days post coitum (dpc), Wnt-1 and Pax-2 are rostrally induced all along the neural plate. Considering that forebrain markers are repressed in embryos treated with RA at the same time, these findings strongly support the idea that RA administration at the late streak stage induces an ordered repatterning of the rostral CNS, possibly altering the A/P nature of mesendodermal inductive signals.

Two homeobox genes, Otx1 and Otx2, act with two other previously identified homeobox genes, Emx1 and Emx2, to control development of the rostral brain in mice and are homologous with orthodenticle and empty spiracle genes in Drosophila. Thus some vertebrate and invertebrate homeobox genes are now known to be homologues. The four genes govern expression of several regions of the brain including the telencephalon. The genes' expression domains progress in the sequence Emx1, Emx2, Otx1 and Otx2.