Kato Laboratory Yoichi Kato, M.D., Ph.D. Nagoya City University Medical School, Japan Florida State University College of Medicine Dept. of Biomedical Sciences 1115 West Call Street Tallahassee, FL 32306-4300 Office: (850) 645-1481, MSR 3300-M Lab: (850) 645-2929, MSR 3310-L Dr. Kato's Faculty Profile
Research Interests
Figure 1. The Notch signaling Pathway We focus on dissecting the role of Notch signaling pathway during development. The Notch signaling pathway is an evolutionally conserved pathway that is involved in many aspects of development and human diseases. This pathway mediates local cell-cell communication and regulates downstream responses, such as cell-fate specification, progenitor cell maintenance, boundary formation, cell proliferation and apoptosis. The proteins of the Notch family are cell-surface single-pass membrane receptors that are activated by the ligands, Delta and Jagged (Jagged is the mammalian homologue of Drosophila Serrate). Upon ligand binding, the intracellular portion of the Notch receptor (Notch IntraCellular Domain; NICD) is proteolytically cleaved and released, translocates into the nucleus, and forms complex with nuclear proteins including a DNA-binding protein called CSL (for human, CBF1; Drosophila, Suppressor of Hairless; C. elegans, Lag-1) and a transcriptional co-activator, Mastermind-like (MAML), to activate the transcription of target genes (Figure 1).
Current Research Projects
Figure 2. The depletion of NBP in Xenopus embryos by Morpholino Oligo (MO) led to the defects of LR asymmetry. A: uninjected embryo, B: Control MO-injected embryo, C: NBP MO-injected embryo (right), D: NBP MO-injected embryo (left) The patterning of left-right asymmetry by Notch signaling While vertebrate seems to be essentially symmetrical on the exterior, there are many interior left-right (LR) asymmetries in the disposition and placement of internal organs. Disorders in this process result in situs inversus viscerum and congenital heart diseases. The Nodal-Pitx2 pathway in the left side of body plays a crucial role during the patterning of LR asymmetry. Nodal, a TGF-b-like signal, is a key molecule which is expressed only in the left side and regulates LR asymmetric patterning. Notch plays dual roles during LR patterning. At the early developmental stage, Notch is a direct regulator of Nodal expression. At the later stage, Notch regulates the expression of another left-side specific gene, Pitx2. Pitx2 has been proposed to maintain the left identity of body. However, the regulatory mechanism of Pitx2 expression by Notch signaling still remains unclear. Recently, we uncovered Notch signaling could suppress the expression of Pitx2 and this activity was inhibited by a Notch- associated protein (NBP) in normal embryos to maintain LR asymmetry (Figure 2). We are further studying this regulatory mechanism of Notch signaling by NBP.
Figure 3. The role of Notch signaling in glial development. Jagged1 and F3/contactin are ligands of Notch receptor. Hes1 and Hes5 are direct targets of Notch signaling. NSC: Neural Stem The downstream mechanism of radial glia formation promoted by Notch signaling Glia are the most abundant cells within the brain and are comprised of both macroglia and microglia. Macroglia provide important developmental, functional, structural, metabolic and trophic support to neurons, and microglia have crucial phagocytic roles in the central nervous system. Radial glia are one of the macroglial subtypes and are identifiable by morphological and molecular characteristics shared with neuroepithelial cells and astrocytes. The classically-observed function of radial glia is to guide neuronal migration during brain development. The migration defect of neurons coincides with the progressive reduction of radial glia cells leads to cortical dysplasia, and the concomitant pathologies of epilepsy and mental retardation. In addition, recent studies have demonstrated that radial glia function as neural progenitor cells in the developing brain and suggest that radial glia cells could be a source of neural stem cells for stem cell based treatment. Therefore, understanding of the mechanisms of radial glia development will contribute to elucidating the molecular nature of glial-based pathologies and developing stem cell-treatment. To date, several factors, which act instructively and promote radial glia formation, have been identified. Notch signal is one of those signals. Notch signal is one of those signals (Figure 3). Based on our observation, both CSL-dependent and CSL-independent pathways mediate Notch signaling during radial glia development. Therefore, we focus that the identification and the characterization of important players in this CSL-independent pathway.
Current Laboratory Members
Masanori Seki, MD, PhD: Postdoctoral Fellow Nilin Gupta: Graduate Student Akiko Kato: Lab Assistant
Selected References
Sakano D, Kato A, Parikh N, McKnight K, Terry D, Stefanovic B and Kato Y. NBP canalizes Notch-dependent transcription, excluding Mastermind-like1 from selected target genes during left-right patterning. Developmental Cell In press. Koide Y, Kiyota T, Tonganunt M, Tonganunt M, Pinkaew D, Liu Z, Kato Y, Towantana N, Phongdara A, FujiseK. Embryonic Lethality of Fortilin-null mutant mice by BMP-pathway overactivation. BBA 2009, 1790: 326-338. Kiyota T, Kato A, Altmann CR, Kato Y. The POU homeobox protein Oct-1 regulates radial glia differentiation downstream of Notch signaling. Developmental Biology 2008, 315: 579-592. Kiyota T, Kato A, Kato Y. Ets-1 regulates radial glia formation during vertebrate embryogenesis. Organogenesis 2007, 3: 93-101. Kato Y, Habas R, Katsuyama Y, Naar AM, He X. A component of the ARC/Mediator complex required for TGF beta/Nodal signalling. Nature. 2002 418:641-6. Kato Y, Shi Y, He X. Neuralization of the Xenopus embryo by inhibition of p300/ CREB-binding protein function. J Neurosci. 1999 19:9364-73.