Vertebrate organogenesis is a complex process that is mediated by a coordinated set of cellular and molecular events. Analyzing these dynamic processes can be particularly difficult in mammalian animal models due to the development of mammalian embryos in utero. However, because of the optical clarity and external fertilization of zebrafish embryos/larvae, this vertebrate animal model system can be used to image in vivo the dynamic cellular processes of how specialized cells organize to become vertebrate organs. Exploiting these particularly useful imaging properties, the zebrafish community including our own lab has developed neural specific transgenic tools to further illuminate the dynamic cellular mechanisms that transform the neuroepithelium/neural tube into mature brain structures. Utilizing these tools, we have initiated a fonward genetic screen with the Gleeson lab to identify novel SBD mutants which may provide further insight into the conserved mechanisms during brain morphogenesis. As a result, we have recovered SBD mutants with early brain defects that harbor mutations in genes that are in the cell polarity pathway further supporting the significance of cell polarization during brain morphogenesis. Because ofthe importance of polarity genes in establishing the cellular organization required for cell shape and movement, we hypothesize that cell polarity regulates the cell morphology and migration of neural cell lineages during CNS/brain development in order to direct overall brain morphogenesis and function.
The Specific Aims of Project III are: 1] Aim 1: To uncover novel cell polarity pathways that may modulate CNS/brain morphogenesis and function;2] Aim 2: To investigate SBD mutations discovered from human genetic studies and mouse forward genetic screens as described in Project I and II, respectively;3] Aim 3: To investigate how cell polarity genes direct neural cell lineage morphology and migration. Overall, our interdisciplinary approach including the utilization of a genetically tractable yet optically transparent animal system, innovative live imaging tools and techniques, and synergies with human and mouse genetic studies will provide in vivo mechanistic insight into how cell polarity may directiy guide neurodevelopment.
The proposed studies are focused to investigate the direct impact of cell polarity on the development of neural specific lineages into a fully mature and functional brain. The combination of zebrafish genetic studies and live animal imaging will reveal novel mechanisms that direct this process and subsequently lead to new diagnostic and therapeutic approaches towards the clinical management of SBDs.
|Zaki, Maha S; Selim, Laila; El-Bassyouni, Hala T et al. (2016) Molybdenum cofactor and isolated sulphite oxidase deficiencies: Clinical and molecular spectrum among Egyptian patients. Eur J Paediatr Neurol 20:714-22|
|Johansen, Anide; Rosti, Rasim O; Musaev, Damir et al. (2016) Mutations in MBOAT7, Encoding Lysophosphatidylinositol Acyltransferase I, Lead to Intellectual Disability Accompanied by Epilepsy and Autistic Features. Am J Hum Genet 99:912-916|
|Scott, Eric M; Halees, Anason; Itan, Yuval et al. (2016) Characterization of Greater Middle Eastern genetic variation for enhanced disease gene discovery. Nat Genet 48:1071-6|
|Rosti, Rasim O; Dikoglu, Esra; Zaki, Maha S et al. (2016) Extending the mutation spectrum for Galloway-Mowat syndrome to include homozygous missense mutations in the WDR73 gene. Am J Med Genet A 170A:992-8|
|Jerber, Julie; Zaki, Maha S; Al-Aama, Jumana Y et al. (2016) Biallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly. Am J Hum Genet 99:1181-1189|
|Li, Hongda; Saucedo-Cuevas, Laura; Regla-Nava, Jose A et al. (2016) Zika Virus Infects Neural Progenitors in the Adult Mouse Brain and Alters Proliferation. Cell Stem Cell 19:593-598|
|Roosing, Susanne; Rosti, Rasim O; Rosti, Basak et al. (2016) Identification of a homozygous nonsense mutation in KIAA0556 in a consanguineous family displaying Joubert syndrome. Hum Genet 135:919-21|
|Li, Hongda; Bielas, Stephanie L; Zaki, Maha S et al. (2016) Biallelic Mutations in Citron Kinase Link Mitotic Cytokinesis to Human Primary Microcephaly. Am J Hum Genet 99:501-10|
|Breuss, Martin W; Sultan, Tipu; James, Kiely N et al. (2016) Autosomal-Recessive Mutations in the tRNA Splicing Endonuclease Subunit TSEN15 Cause Pontocerebellar Hypoplasia and Progressive Microcephaly. Am J Hum Genet 99:228-35|
|Kariminejad, A; SchÃ¶ls, L; SchÃ¼le, R et al. (2016) CYP2U1 mutations in two Iranian patients with activity induced dystonia, motor regression and spastic paraplegia. Eur J Paediatr Neurol 20:782-7|
Showing the most recent 10 out of 57 publications