Research & Publications
Our research is generally concerned with the study of the mechanisms governing the development of the mammalian brain. We are particularly interested in addressing how the perturbation of basic biological processes 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 and structural brain disorders associated with specific genetic lesions. Insight into these questions will shed light on fundamental biological processes and provide information relevant for the design of therapeutic approaches.
Specialized Terms: Mammalian neural development; Mechanisms of brain morphogenesis and pathogenesis; Microcephaly; Structural brain disorders; Cerebrovascular disease; Cerebral cavernous malformations; Notch signaling; CADASIL
Extensive Research Description
Molecular Basis of Brain Disorders
Cerebral Cavernous 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.
Boylan, A. J., DiLuna, M. L., Pricola, K. L., Louvi, A., and Gunel, M. (2008). PDCD10, the gene mutated in Cerebral Cavernous Malformation 3 (CCM3) is expressed in the neurovascular unit. Neurosurgery 62, 930-938.
Chen, L., Tanriover,
G., Yano, H., Friedlander, R., Louvi, A.
and Gunel, M. (2009). Apoptotic functions of PDCD10, the gene mutated in cerebral cavernous malformation 3. Stroke 40, 1474-1481.
Chen, L., Two, A. M., Zhang, H., Min, W., and Günel, M.* (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.
- Louvi, A.*, Nishimura, S. and Gunel, M. (2014). Ccm3, a gene associated with cerebral cavernous malformations, is required for neuronal migration. Development, 141, 1404-1415.
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 and stem cell models.
- Bilgüvar, K.*, Oztürk, A. K.*, Louvi, A., Kwan, K. Y., Choi, M., Tatli, B., Yalnizoglu, D., Tüysüz, B., Caglayan, A. O., Gökben, S., Kaymakçalan, H., Barak, T., Bakircioglu, M., Yasuno, K., Ho, W., Sanders, S., Zhu, Y., Yilmaz, S., Dinçer, A., Johnson, M. H., Bronen, R. A., Koçer, N., Per, H., Mane, S., Pamir, M. N., Yalçinkaya, C., Kumandas, S., Topçu, M., Ozmen, M., Sestan, N., Lifton, R. P., State, M. W., and Günel, M. (2010). Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature 467, 207-210.
- Barak, T.*, Kwan, K. Y.*, Louvi, A., Demirbilek, V., Saygi, S., Tüysüz, B., Choi, M., Boyaci, H., Doerschner, K., Zhu, Y., Kaymakçalan, H., Yilmaz, S., Bakircioglu, M., Çaglayan, A. O., Öztürk, A. K., Yasuno, K., Brunken, W. J., Atalar, E., Yalçinkaya, C., Dinçer, A., Bronen, R. A., Mane, S., Özçelik, T., Lifton, R. P., Šestan, N., Bilgüvar, K., and Günel, M. (2011). Recessive laminin g3 mutations cause malformations of occipital cortical development. Nat. Genet. 43, 590-594.
- Bilguvar K, Tyagi NK, Ozkara C, Tuysuz B, Bakircioglu M, Choi M, Delil S, Caglayan AO, Baranoski JF, Erturk O, Yalcinkaya C, Karacorlu M, Dincer A, Johnson MH, Mane S, Chandra SS, Louvi A, Boggon TJ, Lifton RP, Horwich AL, Gunel M. (2013) Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration. Proc. Natl. Acad. Sci. USA, 110(9):3489-94.
- Mishra-Gorur, K., Caglayan, A. O., Schaffer, A., Chabu, C., Henegariu, O., Vonhoff, F., Akgumus, G. T., Nishimura, S., Han, W., Tu, S., Baran, B., Gumus, H., Cengiz., D., Zaki, M., Hossni, H., Riviere, J.-B., Kayserili, H., Spencer, E., Rosti, R., Schroth, J., Per, H., Caglar, C., Caglar, C., Dolen, D., Baranoski, J., Kumandas, S., Minja, F., Erson-Omay, E. Z., Mane, S., Lifton, R., Xu, T., Keshishian, H., Dobyns, W., Chi, N., Sestan, N., Louvi, A., Bilguvar, K., Yasuno, K., Gleeson, J., and Gunel, M. (2014) Mutations in KATNB1 cause complex cerebral malformations by disrupting asymmetrically dividing neural progenitors. Neuron, 84, 1226-1239.
Notch Lineages in the Mammalian Brain
The Notch signaling pathway is an evolutionarily conserved cell interaction mechanism that is active in a wide range of organisms and tissues, is associated with early lineage decisions, and affects CNS development at many different levels, including neuronal progenitor maintenance, cell fate decisions between neuronal and glial lineages, terminally differentiated neuron behavior, as well as patterning of cellular fields. We are comprehensively characterizing the contributions of cellular lineages that depend on Notch activity in the developing and adult brain by utilizing a unique set of transgenic mice generated in the laboratory of Dr. Spyros Artavanis-Tsakonas (Harvard Medical School).
- Louvi, A. and Artavanis-Tsakonas, S. (2006). Notch signalling in vertebrate neural development. Nat. Rev. Neurosci. 7, 93-102.
- Louvi, A.* and Artavanis-Tsakonas, S.* (2012). Notch and disease: A growing field. Semin. Cell Dev. Biol 23(4):473-80. doi: 10.1016/j.semcdb.2012.02.005. Epub 2012 Feb 20.
- Molecular Mechanisms of Primary Microcephaly
- The Biology and Pathobiology of CCM3
- Notch Lineages in Mammalian Brain (in collaboration with S. Artavanis-Tsakonas, Harvard Medical School)
Brain; Microcephaly; Morphogenesis; Nervous System Diseases; Neurosurgery; Hemangioma, Cavernous, Central Nervous System; CADASIL; Diseases