Yale School of Medicine

Neurosurgery

Louvi Research, Neurosurgery

Louvi Research, Neurosurgery

Neurosurgery
P.O., Box 208082
New Haven, CT 06520-8082
Tel: 203.785.2805
Fax: 203.785.6916
neurosurgery@yale.edu

Mechanisms of Brain Morphogenesis and Pathogensis

Our research is generally concerned with the study of molecular mechanisms governing the development of the vertebrate brain. We are particularly interested in addressing how the perturbation of basic biological mechanisms leads to clinically significant brain pathologies. Working closely with other research groups in the Yale Program on Neurogenetics, we study the molecular and cellular mechanisms underlying neurodevelopmental disorders associated with specific genetic lesions. Insight into these questions will shed light on fundamental neurodevelopmental processes and provide information relevant for the design of therapeutic approaches.

Molecular Basis of Brain Disorders

With the Günel Lab (Program on Neurogenetics, Neurosurgery, Neurobiology and Genetics)

Cerebral Carvernous Malformations (CCM). We are investigating the biology of Ccm3, one of three genes implicated in the pathogenesis of CCM, a monogenic cerebrovascular disorder. We have generated a mouse model that develops vascular lesions highly similar to human cavernomas; its study has led to the identification of cell autonomous as well as cell non-autonomous functions of CCM3 in vascular and neural development, and has unraveled an important role of this protein in the neurovascular unit.

  • Tanriover et al. (2008). PDCD10, the gene mutated in Cerebral Cavernous Malformation 3 (CCM3) is expressed in the neurovascular unit. Neurosurgery 62, 930-938.
  • Chen et al. (2009). Apoptotic functions of PDCD10, the gene mutated in cerebral cavernous malformation 3. Stroke 40, 1474-1481.
  • Louvi et al. (2011). Loss of cerebral cavernous malformation 3 (Ccm3) in neuroglia leads to CCM and vascular pathology. Proc. Natl. Acad. Sci. USA. 108, 3737-3742.
  • Oztürk, Louvi, and Günel (2011). Genetics of Cerebral Cavernous Malformations. In Youmans Neurological Surgery, 6th edition, ed. H. R. Winn, Elsevier.

Disorders of Cortical Development. Several novel genes implicated in human cortical development have been identified in the Günel lab using genetic analyses and next generation sequencing. We are using in vitro and in vivo approaches to examine the biology of these genes and are characterizing relevant animal models.

  • Bilguvar, Oztürk, et al. (2010). Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature 467, 207-210.
  • Barak, Kwan, et al. (2011). Recessive LAMC3 mutations cause malformations of occipital cortical development. Nat. Genet. 43, 590-594.

With the State Lab (Program on Neurogenetics, Child Study Center, Psychiatry and Genetics)

Tourette syndrome. Using genetic evidence obtained in the State lab as a starting point, our collaborative work aims at elucidating the biology of SLITRK1 (SLIT and Trk-like family 1), a gene involved in rare cases of Tourette syndrome, a developmental neuropsychiatric disorder. We are using molecular and cell biological approaches as well as animal models to characterize the functions of Slitrk1 in brain development and explore the impact of disease-linked variants on brain morphogenesis and maturation.

  • Abelson, Kwan, O'Roak, et al. (2005). Sequence variants in SLITRK1 are associated with Tourette's syndrome. Science 310, 317-320.
  • Stillman, Krsnik, et al. (2009). Developmentally regulated and evolutionarily conserved expression of SLITRK1 in brain circuits implicated in Tourette syndrome. J. Comp. Neurol. 513, 21-37.

With the Artavanis-Tsakonas Lab (Cell Biology, Harvard Medical School)

CADASIL. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy, the most common monogenic form of ischemic cerebral small-vessel disease, is associated with highly stereotypical mutations in the extracellular domain of the Notch 3 receptor. Our recent work has demonstrated that two phenotypically distinct mutations define different hypomorphic activity states of the receptor. Transgenic mice expressing the mutant receptors in vascular smooth muscle cells develop a spectrum of phenotypes that parallel remarkably the human condition. We are currently investigating the molecular and cellular biology of Notch signaling in vascular smooth muscle cells.


Morphogenesis Of Brain Barriers

Blood-tissue barriers are the major interfaces between the central nervous system and peripheral circulation. Barriers are found in the endothelium of the brain vasculature (the blood-brain barrier) and the epithelium of the choroid plexus (the blood-CSF barrier). We are studying the cellular and molecular mechanisms responsible for the establishment of brain barriers during embryogenesis using the mouse as our main experimental system. Our specific goal is to gain insight into the blood-CSF barrier by embryologic, genetic, and molecular analyses of the choroid plexus while exploring its known relationship to the development of hydrocephalus, a common neurodevelopmental problem that requires surgical intervention.