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Kaya Bilguvar,
Navneet K Tyagi,
Cigdem Ozkara,
Beyhan Tuysuz,
Mehmet Bakircioglu,
Murim Choi,
Sakir Delil,
Ahmet O Caglayan,
Jacob F Baranoski,
Ozdem Erturk, [......],
Murat Karacorlu,
Alp Dincer,
Michele H Johnson,
Shrikant Mane,
Sreeganga S Chandra, Angeliki Louvi,
Titus J Boggon,
Richard P Lifton,
Arthur L Horwich,
Murat Gunel
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ABSTRACT: Ubiquitin C-terminal hydrolase-L1 (UCHL1), a neuron-specific de-ubiquitinating enzyme, is one of the most abundant proteins in the brain. We describe three siblings from a consanguineous union with a previously unreported early-onset progressive neurodegenerative syndrome featuring childhood onset blindness, cerebellar ataxia, nystagmus, dorsal column dysfuction, and spasticity with upper motor neuron dysfunction. Through homozygosity mapping of the affected individuals followed by whole-exome sequencing of the index case, we identified a previously undescribed homozygous missense mutation within the ubiquitin binding domain of UCHL1 (UCHL1(GLU7ALA)), shared by all affected subjects. As demonstrated by isothermal titration calorimetry, purified UCHL1(GLU7ALA), compared with WT, exhibited at least sevenfold reduced affinity for ubiquitin. In vitro, the mutation led to a near complete loss of UCHL1 hydrolase activity. The GLU7ALA variant is predicted to interfere with the substrate binding by restricting the proper positioning of the substrate for tunneling underneath the cross-over loop spanning the catalytic cleft of UCHL1. This interference with substrate binding, combined with near complete loss of hydrolase activity, resulted in a >100-fold reduction in the efficiency of UCHL1(GLU7ALA) relative to WT. These findings demonstrate a broad requirement of UCHL1 in the maintenance of the nervous system.
Proceedings of the National Academy of Sciences 01/2013; · 9.68 Impact Factor
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ABSTRACT: Signals through the Notch receptors are used throughout development to control cellular fate choices. Our intention here is to provide an overview of the involvement of Notch signaling in human disease, which, keeping pace with the known biology of the pathway, manifests itself in a pleiotropic fashion. A pathway with such broad action in normal development, a profound involvement in the biology of adult stem cells and intricate and complex controls governing its activity, poses numerous challenges. We provide an overview of Notch related pathologies identified thus far and emphasize aspects that have been modeled in experimental systems in order to understand the underlying pathobiology and, hopefully, help the definition of rational therapeutic avenues.
Seminars in Cell and Developmental Biology 02/2012; 23(4):473-80. · 6.65 Impact Factor
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ABSTRACT: NKCC1 and KCC2, related cation-chloride cotransporters (CCC), regulate cell volume and γ-aminobutyric acid (GABA)-ergic neurotranmission by modulating the intracellular concentration of chloride [Cl(-)]. These CCCs are oppositely regulated by serine-threonine phosphorylation, which activates NKCC1 but inhibits KCC2. The kinase(s) that performs this function in the nervous system are not known with certainty. WNK1 and WNK4, members of the WNK (with no lysine [K]) kinase family, either directly or via the downstream SPAK/OSR1 Ste20-type kinases, regulate the furosemide-sensitive NKCC2 and the thiazide-sensitive NCC, kidney-specific CCCs. What role the novel WNK2 kinase plays in this regulatory cascade, if any, is unknown. Here, we show that WNK2, unlike other WNKs, is not expressed in kidney; rather, it is a neuron-enriched kinase primarily expressed in neocortical pyramidal cells, thalamic relay cells, and cerebellar granule and Purkinje cells in both the developing and adult brain. Bumetanide-sensitive and Cl(-)-dependent (86)Rb(+) uptake assays in Xenopus laevis oocytes revealed that WNK2 promotes Cl(-) accumulation by reciprocally activating NKCC1 and inhibiting KCC2 in a kinase-dependent manner, effectively bypassing normal tonicity requirements for cotransporter regulation. TiO(2) enrichment and tandem mass spectrometry studies demonstrate WNK2 forms a protein complex in the mammalian brain with SPAK, a known phosphoregulator of NKCC1. In this complex, SPAK is phosphorylated at Ser-383, a consensus WNK recognition site. These findings suggest a role for WNK2 in the regulation of CCCs in the mammalian brain, with implications for both cell volume regulation and/or GABAergic signaling.
Journal of Biological Chemistry 08/2011; 286(34):30171-80. · 4.77 Impact Factor
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Tanyeri Barak,
Kenneth Y Kwan, Angeliki Louvi,
Veysi Demirbilek,
Serap Saygı,
Beyhan Tüysüz,
Murim Choi,
Hüseyin Boyacı,
Katja Doerschner,
Ying Zhu, [......],
Ergin Atalar,
Cengiz Yalçınkaya,
Alp Dinçer,
Richard A Bronen,
Shrikant Mane,
Tayfun Ozçelik,
Richard P Lifton,
Nenad Sestan,
Kaya Bilgüvar,
Murat Günel
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ABSTRACT: The biological basis for regional and inter-species differences in cerebral cortical morphology is poorly understood. We focused on consanguineous Turkish families with a single affected member with complex bilateral occipital cortical gyration abnormalities. By using whole-exome sequencing, we initially identified a homozygous 2-bp deletion in LAMC3, the laminin γ3 gene, leading to an immediate premature termination codon. In two other affected individuals with nearly identical phenotypes, we identified a homozygous nonsense mutation and a compound heterozygous mutation. In human but not mouse fetal brain, LAMC3 is enriched in postmitotic cortical plate neurons, localizing primarily to the somatodendritic compartment. LAMC3 expression peaks between late gestation and late infancy, paralleling the expression of molecules that are important in dendritogenesis and synapse formation. The discovery of the molecular basis of this unusual occipital malformation furthers our understanding of the complex biology underlying the formation of cortical gyrations.
Nature Genetics 06/2011; 43(6):590-4. · 35.53 Impact Factor
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Joseph F Arboleda-Velasquez,
Jan Manent,
Jeong Hyun Lee,
Saara Tikka,
Carolina Ospina,
Charles R Vanderburg,
Matthew P Frosch,
Manuel Rodríguez-Falcón,
Judit Villen,
Steven Gygi,
Francisco Lopera,
Hannu Kalimo,
Michael A Moskowitz,
Cenk Ayata, Angeliki Louvi,
Spyros Artavanis-Tsakonas
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ABSTRACT: The most common monogenic cause of small-vessel disease leading to ischemic stroke and vascular dementia is the neurodegenerative syndrome cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is associated with mutations in the Notch 3 receptor. CADASIL pathology is characterized by vascular smooth muscle cell degeneration and accumulation of diagnostic granular osmiophilic material (GOM) in vessels. The functional nature of the Notch 3 mutations causing CADASIL and their mechanistic connection to small-vessel disease and GOM accumulation remain enigmatic. To gain insight into how Notch 3 function is linked to CADASIL pathophysiology, we studied two phenotypically distinct mutations, C455R and R1031C, respectively associated with early and late onset of stroke, by using hemodynamic analyses in transgenic mouse models, receptor activity assays in cell culture, and proteomic examination of postmortem human tissue. We demonstrate that the C455R and R1031C mutations define different hypomorphic activity states of Notch 3, a property linked to ischemic stroke susceptibility in mouse models we generated. Importantly, these mice develop osmiophilic deposits and other age-dependent phenotypes that parallel remarkably the human condition. Proteomic analysis of human brain vessels, carrying the same CADASIL mutations, identified clusterin and collagen 18 α1/endostatin as GOM components. Our findings link loss of Notch signaling with ischemic cerebral small-vessel disease, a prevalent human condition. We determine that CADASIL pathophysiology is associated with hypomorphic Notch 3 function in vascular smooth muscle cells and implicate the accumulation of clusterin and collagen 18 α1/endostatin in brain vessel pathology.
Proceedings of the National Academy of Sciences 05/2011; 108(21):E128-35. · 9.68 Impact Factor
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ABSTRACT: The primary cilium is a cellular organelle that is almost ubiquitous in eukaryotes, yet its functions in vertebrates have been slow to emerge. The last fifteen years have been marked by accelerating insight into the biology of primary cilia, arising from the synergy of three major lines of research. These research programs describe a specialized mode of protein trafficking in cilia, reveal that genetic disruptions of primary cilia cause complex human disease syndromes, and establish that Sonic hedgehog (Shh) signal transduction requires the primary cilium. New lines of research have branched off to investigate the role of primary cilia in neuronal signaling, adult neurogenesis, and brain tumor formation. We review a fast expanding literature to determine what we now know about the primary cilium in the developing and adult CNS and what new directions should lead to further clarity.
Neuron 03/2011; 69(6):1046-60. · 14.74 Impact Factor
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ABSTRACT: Communication between neural cells and the vasculature is integral to the proper development and later function of the central nervous system. A mechanistic understanding of the interactions between components of the neurovascular unit has implications for various disorders, including cerebral cavernous malformations (CCMs) in which focal vascular lesions form throughout the central nervous system. Loss of function mutations in three genes with proven endothelial cell autonomous roles, CCM1/krev1 interaction trapped gene 1, CCM2, and CCM3/programmed cell death 10, cause familial CCM. By using neural specific conditional mouse mutants, we show that Ccm3 has both neural cell autonomous and nonautonomous functions. Gfap- or Emx1-Cre-mediated Ccm3 neural deletion leads to increased proliferation, increased survival, and activation of astrocytes through cell autonomous mechanisms involving activated Akt signaling. In addition, loss of neural CCM3 results in a vascular phenotype characterized by diffusely dilated and simplified cerebral vasculature along with formation of multiple vascular lesions that closely resemble human cavernomas through cell nonautonomous mechanisms. RNA sequencing of the vascular lesions shows abundant expression of molecules involved in cytoskeletal remodeling, including protein kinase A and Rho-GTPase signaling. Our findings implicate neural cells in the pathogenesis of CCMs, showing the importance of this pathway in neural/vascular interactions within the neurovascular unit.
Proceedings of the National Academy of Sciences 02/2011; 108(9):3737-42. · 9.68 Impact Factor
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ABSTRACT: The conserved role of Notch signaling in controlling intestinal cell fate specification and homeostasis has been extensively studied. Nevertheless, the precise identity of the cells in which Notch signaling is active and the role of different Notch receptor paralogues in the intestine remain ambiguous, due to the lack of reliable tools to investigate Notch expression and function in vivo. We generated a new series of transgenic mice that allowed us, by lineage analysis, to formally prove that Notch1 and Notch2 are specifically expressed in crypt stem cells. In addition, a novel Notch reporter mouse, Hes1-EmGFP(SAT), demonstrated exclusive Notch activity in crypt stem cells and absorptive progenitors. This roster of knock-in and reporter mice represents a valuable resource to functionally explore the Notch pathway in vivo in virtually all tissues.
PLoS ONE 01/2011; 6(10):e25785. · 4.09 Impact Factor
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Kenneth Y Kwan, Angeliki Louvi,
Veysi Demirbilek,
Serap Saygı,
Beyhan Tüysüz,
Murim Choi,
Hüseyin Boyacı,
Katja Doerschner,
Ying Zhu [......] Ergin Atalar,
Cengiz Yalçınkaya,
Alp Dinçer,
Richard A Bronen,
Shrikant Mane,
Tayfun Ozçelik,
Richard P Lifton,
Nenad Sestan,
Kaya Bilgüvar,
Murat Günel Nature genetics
Nature genetics. 01/2011;
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Kaya Bilgüvar,
Ali Kemal Oztürk, Angeliki Louvi,
Kenneth Y Kwan,
Murim Choi,
Burak Tatli,
Dilek Yalnizoğlu,
Beyhan Tüysüz,
Ahmet Okay Cağlayan,
Sarenur Gökben, [......],
Shrikant Mane,
Mehmet Necmettin Pamir,
Cengiz Yalçinkaya,
Sefer Kumandaş,
Meral Topçu,
Meral Ozmen,
Nenad Sestan,
Richard P Lifton,
Matthew W State,
Murat Günel
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ABSTRACT: The development of the human cerebral cortex is an orchestrated process involving the generation of neural progenitors in the periventricular germinal zones, cell proliferation characterized by symmetric and asymmetric mitoses, followed by migration of post-mitotic neurons to their final destinations in six highly ordered, functionally specialized layers. An understanding of the molecular mechanisms guiding these intricate processes is in its infancy, substantially driven by the discovery of rare mutations that cause malformations of cortical development. Mapping of disease loci in putative Mendelian forms of malformations of cortical development has been hindered by marked locus heterogeneity, small kindred sizes and diagnostic classifications that may not reflect molecular pathogenesis. Here we demonstrate the use of whole-exome sequencing to overcome these obstacles by identifying recessive mutations in WD repeat domain 62 (WDR62) as the cause of a wide spectrum of severe cerebral cortical malformations including microcephaly, pachygyria with cortical thickening as well as hypoplasia of the corpus callosum. Some patients with mutations in WDR62 had evidence of additional abnormalities including lissencephaly, schizencephaly, polymicrogyria and, in one instance, cerebellar hypoplasia, all traits traditionally regarded as distinct entities. In mice and humans, WDR62 transcripts and protein are enriched in neural progenitors within the ventricular and subventricular zones. Expression of WDR62 in the neocortex is transient, spanning the period of embryonic neurogenesis. Unlike other known microcephaly genes, WDR62 does not apparently associate with centrosomes and is predominantly nuclear in localization. These findings unify previously disparate aspects of cerebral cortical development and highlight the use of whole-exome sequencing to identify disease loci in settings in which traditional methods have proved challenging.
Nature 09/2010; 467(7312):207-10. · 36.28 Impact Factor
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Kaya,
Ali Kemal, Angeliki Louvi,
Kenneth Y. Kwan,
Murim Choi,
Burak,
Dilek,
Beyhan,
Ahmet Okay,
Sarenur, [......],
Per,
Shrikant Mane,
Mehmet Necmettin Pamir,
Cengiz,
Sefer,
Meral,
Nenad,
Richard P. Lifton,
Matthew W. State,
Murat
Nature 08/2010; 467(7312):207-210. · 36.28 Impact Factor
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A Gulhan Ercan-Sencicek,
Althea A Stillman,
Ananda K Ghosh,
Kaya Bilguvar,
Brian J O'Roak,
Christopher E Mason,
Thomas Abbott,
Abha Gupta,
Robert A King,
David L Pauls, [......],
Thomas Fernandez,
Stephan Sanders, Angeliki Louvi,
Judy H Cho,
Shrikant Mane,
Christopher M Colangelo,
Thomas Biederer,
Richard P Lifton,
Murat Gunel,
Matthew W State
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ABSTRACT: Tourette's syndrome is a common developmental neuropsychiatric disorder characterized by chronic motor and vocal tics. Despite a strong genetic contribution, inheritance is complex, and risk alleles have proven difficult to identify. Here, we describe an analysis of linkage in a two-generation pedigree leading to the identification of a rare functional mutation in the HDC gene encoding L-histidine decarboxylase, the rate-limiting enzyme in histamine biosynthesis. Our findings, together with previously published data from model systems, point to a role for histaminergic neurotransmission in the mechanism and modulation of Tourette's syndrome and tics.
New England Journal of Medicine 05/2010; 362(20):1901-8. · 53.30 Impact Factor
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ABSTRACT: Mutations in the Programmed Cell Death 10 (PDCD10) gene cause autosomal dominant familial cerebral cavernous malformations (CCM3). To date, little is known about the function of this gene and its role in disease pathogenesis.
We examined the effects of overexpression of wild-type and 2 human disease-causing variants of PDCD10 on cell death using 3 different methods (TUNEL and MTT assays and caspase-3 activation). We analyzed expression of CCM3, activated caspase-3, and p38 in endothelial cell lines using the serum deprivation model of apoptosis induction. Finally, we assayed the effects of siRNA-mediated inhibition of endogenous PDCD10 expression on cell death in endothelial cell cultures.
Overexpression of wild-type CCM3, but not disease-linked mutant forms, induced apoptosis as confirmed by TUNEL and increased levels of activated caspase-3. Serum starvation of endothelial cells, an inducer of apoptosis, led to increased expression of CCM3 and activation of p38 and ultimately activated caspase-3. siRNA-mediated inhibition of CCM3 expression resulted in decreased levels of p38 and activated caspase-3, and decreased cell death.
CCM3 is both necessary and sufficient to induce apoptosis in vitro in well-defined cell culture systems. Even though it is currently unclear whether this effect on apoptosis is direct or indirect through modulation of cell cycle, these results led to the novel hypothesis that CCM lesions may form as a consequence of aberrant apoptosis, potentially altering the balance between the endothelium and neural cells within the neurovascular unit.
Stroke 03/2009; 40(4):1474-81. · 5.73 Impact Factor
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ABSTRACT: Tourette syndrome (TS) is an inherited developmental neuropsychiatric disorder characterized by vocal and motor tics. Multiple lines of neurophysiological evidence implicate dysfunction in the corticostriatal-thalamocortical circuits in the etiology of TS. We recently identified rare sequence variants in the Slit and Trk-like family member 1 (SLITRK1) gene associated with TS. SLITRK1, a single-pass transmembrane protein, displays similarities to the SLIT family of secreted ligands, which have roles in axonal repulsion and dendritic patterning, but its function and developmental expression remain largely unknown. Here we provide evidence that SLITRK1 has a developmentally regulated expression pattern in projection neurons of the corticostriatal-thalamocortical circuits. SLITRK1 is further enriched in the somatodendritic compartment and cytoplasmic vesicles of cortical pyramidal neurons in mouse, monkey, and human brain, observations suggestive of an evolutionarily conserved function in mammals. SLITRK1 is transiently expressed in the striosomal/patch compartment of the mammalian striatum and moreover is associated with the direct output pathway; adult striatal expression is confined to cholinergic interneurons. These analyses demonstrate that the expression of SLITRK1 is dynamic and specifically associated with the circuits most commonly implicated in TS and related disorders, suggesting that SLITRK1 contributes to the development of corticostriatal-thalamocortical circuits.
The Journal of Comparative Neurology 01/2009; 513(1):21-37. · 3.81 Impact Factor
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Sekiya Shibazaki,
Zhiheng Yu,
Saori Nishio,
Xin Tian,
R Brent Thomson,
Michihiro Mitobe, Angeliki Louvi,
Heino Velazquez,
Shuta Ishibe,
Lloyd G Cantley,
Peter Igarashi,
Stefan Somlo
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ABSTRACT: Polycystic kidney disease (ADPKD) results from failure of the kidney to properly maintain three-dimensional structure after loss of either polycystin-1 or -2. Mice with kidney selective inactivation of Pkd1 during embryogenesis develop profound renal cystic disease and die from renal failure within 3 weeks of birth. In this model, cysts form exclusively from cells in which Cre recombinase is active, but the apparent pace of cyst expansion varies by segment and cell type. Intercalated cells do not participate in cyst expansion despite the presence of cilia up to at least postnatal day 21. Cystic segments show a persistent increase in proliferation as determined by bromodeoxyuridine (BrdU) incorporation; however, the absolute proliferative index is dependent on the underlying proliferative potential of kidney tubule cells. Components of the extracellular regulated kinase (MAPK/ERK) pathway from Ras through MEK1/2 and ERK1/2 to the effector P90(RSK) are activated in both perinatal Pkd1 and adult Pkd2 ortholgous gene disease models. The pattern of MAPK/ERK activation is focal and does not correlate with the pattern of active proliferation identified by BrdU uptake. The possibility of a causal relationship between ERK1/2 activation and cyst cell proliferation was assessed in vivo in the acute perinatal Pkd1 model of ADPKD using MEK1/2 inhibitor U0126. U0126 treatment had no effect on progression of cyst formation in this model at doses sufficient to reduce phospho-ERK1/2 in cystic kidneys. Cysts in ADPKD exhibit both increased proliferation and activation of MAPK/ERK, but cyst growth is not prevented by inhibition of ERK1/2 activation.
Human Molecular Genetics 07/2008; 17(11):1505-16. · 7.64 Impact Factor
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ABSTRACT: Mutations in the programmed cell death 10 gene, PDCD10, cause the autosomal-dominant familial cerebral cavernous malformation 3 (CCM3). Little is known about the function of this gene in disease pathogenesis.
As a first step, we analyzed the messenger ribonucleic acid (mRNA) expression of CCM3 in the embryonic and postnatal mouse brain by in situ hybridization. We generated and characterized CCM3-specific polyclonal antibodies and analyzed CCM3 protein expression in human cerebral and solid organ (extracerebral) tissues using immunohistochemistry.
In embryonic mouse brain, CCM3 mRNA is seen in the ventricular, subventricular, and intermediate zones, the cortical plate, the developing septum, striatum, midbrain, pons, cerebellum, and medulla. In the postnatal mouse brain, we detected CCM3/PDCD10 expression in the olfactory bulb, neocortex, striatum, septal nuclei, hippocampus, dentate gyrus, thalamic and hypothalamic nuclei, inferior colliculus, Purkinje and granule cell layers and deep nuclei of the cerebellum, and in many cells and nuclei in the medulla. Similar to CCM1 and CCM2, the CCM3/PDCD10 protein is expressed in the neurovascular unit but weakly in venous structures within cortical, subcortical, and brainstem tissue. CCM3/PDCD10 protein is strongly expressed in arterial endothelium but weakly or not at all in venous endothelium of extracerebral tissue.
The expression pattern of CCM3/PDCD10 in multiple organ systems displays similarities to CCM1 and CCM2. PDCD10/CCM3 is highly expressed in the neurovascular unit and in the arterial endothelium of structures within multiple organ systems, including the brain. These data provide additional information about CCM3 expression and its role in lesion development and pathogenesis.
Neurosurgery 05/2008; 62(4):930-8; discussion 938. · 2.79 Impact Factor
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Joseph F Arboleda-Velasquez,
Zhipeng Zhou,
Hwa Kyoung Shin, Angeliki Louvi,
Hyung-Hwan Kim,
Sean I Savitz,
James K Liao,
Salvatore Salomone,
Cenk Ayata,
Michael A Moskowitz,
Spyros Artavanis-Tsakonas
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ABSTRACT: Vascular smooth muscle cells (SMCs) have been implicated in the pathophysiology of stroke, the third most common cause of death and the leading cause of long-term neurological disability in the world. However, there is little insight into the underlying cellular pathways that link SMC function to brain ischemia susceptibility. Using a hitherto uncharacterized knockout mouse model of Notch 3, a Notch signaling receptor paralogue highly expressed in vascular SMCs, we uncover a striking susceptibility to ischemic stroke upon challenge. Cellular and molecular analyses of vascular SMCs derived from these animals associate Notch 3 activity to the expression of specific gene targets, whereas genetic rescue experiments unambiguously link Notch 3 function in vessels to the ischemic phenotype.
Proceedings of the National Academy of Sciences 04/2008; 105(12):4856-61. · 9.68 Impact Factor
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Betul Bakkaloglu,
Brian J O'Roak, Angeliki Louvi,
Abha R Gupta,
Jesse F Abelson,
Thomas M Morgan,
Katarzyna Chawarska,
Ami Klin,
A Gulhan Ercan-Sencicek,
Althea A Stillman,
Gamze Tanriover,
Brett S Abrahams,
Jackie A Duvall,
Elissa M Robbins,
Daniel H Geschwind,
Thomas Biederer,
Murat Gunel,
Richard P Lifton,
Matthew W State
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ABSTRACT: Autism spectrum disorders (ASD) are a group of related neurodevelopmental syndromes with complex genetic etiology. We identified a de novo chromosome 7q inversion disrupting Autism susceptibility candidate 2 (AUTS2) and Contactin Associated Protein-Like 2 (CNTNAP2) in a child with cognitive and social delay. We focused our initial analysis on CNTNAP2 based on our demonstration of disruption of Contactin 4 (CNTN4) in a patient with ASD; the recent finding of rare homozygous mutations in CNTNAP2 leading to intractable seizures and autism; and in situ and biochemical analyses reported herein that confirm expression in relevant brain regions and demonstrate the presence of CNTNAP2 in the synaptic plasma membrane fraction of rat forebrain lysates. We comprehensively resequenced CNTNAP2 in 635 patients and 942 controls. Among patients, we identified a total of 27 nonsynonymous changes; 13 were rare and unique to patients and 8 of these were predicted to be deleterious by bioinformatic approaches and/or altered residues conserved across all species. One variant at a highly conserved position, I869T, was inherited by four affected children in three unrelated families, but was not found in 4010 control chromosomes (p = 0.014). Overall, this resequencing data demonstrated a modest nonsignificant increase in the burden of rare variants in cases versus controls. Nonetheless, when viewed in light of two independent studies published in this issue of AJHG showing a relationship between ASD and common CNTNAP2 alleles, the cytogenetic and mutation screening data suggest that rare variants may also contribute to the pathophysiology of ASD, but place limits on the magnitude of this contribution.
The American Journal of Human Genetics 02/2008; 82(1):165-73. · 10.60 Impact Factor
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ABSTRACT: The dorsal midline of the vertebrate neural tube is a source of signals that direct cell fate specification and proliferation. Using genetic fate mapping in the mouse and a previously generated Wnt3aCre line, we report here that genetically labeled cells of the Wnt3a lineage migrate widely from the dorsal midline into the dorsal half of the adult brain and spinal cord, contributing to diverse structures in the diencephalon, midbrain, and brainstem and extensively populating the rostral spinal cord. Conspicuously, many of these structures are linked in specific functional networks. Wnt3a lineage cells populate nuclei of the central auditory system from the medulla to thalamus, and the trigeminal sensory system from the cervical spinal cord to the midbrain. Our findings reveal the rich contributions of the Wnt3a lineage to a variety of brain structures and show that functionally integrated nuclei can share a molecular identity, provided by transient gene expression early in their development.
The Journal of Comparative Neurology 11/2007; 504(5):550-69. · 3.81 Impact Factor
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ABSTRACT: Signals through the Notch receptors are used throughout development to control cellular fate choices. Loss- and gain-of-function studies revealed both the pleiotropic action of the Notch signalling pathway in development and the potential of Notch signals as tools to influence the developmental path of undifferentiated cells. As we review here, Notch signalling affects the development of the nervous system at many different levels. Understanding the complex genetic circuitry that allows Notch signals to affect specific cell fates in a context-specific manner defines the next challenge, especially as such an understanding might have important implications for regenerative medicine.
Nature reviews. Neuroscience 03/2006; 7(2):93-102. · 30.44 Impact Factor
