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 - Basic Medicine (Core Departments) - Anatomical Science
Anatomy and Developmental Biology
Vertebrate body has quite complex structures, which are generated by the process called “morphogenesis”. The mechanism of morphogenesis is still not well understood even in this post-genome era. Alternative splicing of pre-mRNA generates a highly dynamic human proteome through networks of coordinated splicing events, and is regulated on tissu-specific stage-dependent way.Our goal is to establish a new paradigm on the mechanism of morphogenesis from the view point of mRNA processing regulation. We will also try to find chemical modifiers of mRNA splicing, which will be applicable for clinical therapy against malignant tumors, virus infections and neuromuscular diseases caused by aberrant splicing. We welcome enthusiastic young researchers who will charange to open new fields of biology.

 
 
Research and Education
1)Decipherment of splicing code
Recent whole genome sequence analyses revealed that a high degree of proteomic complexity is achieved with a limited number of genes. This surprising finding underscores the importance of alternative splicing, through which a single gene can generate structurally and functionally distinct protein isoforms. Alternative splicing events are dynamically regulated in developmental stage-dependent and tissue specific manners. Pre-mRNAs contain a ‘‘splicing code’’ made up of loosely defined consensus sequences that define the splice junctions and a bewildering number and diversity of relatively short cis-acting elements within exons as well as introns. To decipher the splicing code, we have developed transgenic alternative splicing reporter systems that enable us to visualize alternative splicing events in living nematode. With this reporter system, we have identified trans-acting factors and cis-elements involved in the splicing regulation and found some evolutionally conserved regulation mechanisms of alternative splicing.We recently developed transgenic reporter mice that enable us to visualize dynamic alternative splicing events in single cell resolution.
2) Development of new drugs to cure RNA diseases
There is a growing awareness that misregulations of mRNA processing are causative of many human diseases including hereditary, inflammatory and tumorigenic diseases. Thus new therapeutic approaches that target RNA processing mechanisms are highly anticipated. We focused on the mRNA splicing process, and have developed compounds that alter the alternative splicing events or even reverse some misregulated splicing events. Using splicing reporter systems, we screen and select chemical modifiers of splicing, examine their biological function during developmental stages, and consider their applications to crure hitherto intractable diseases.
3) Mathematical modeling of spontaneous pattern formation process during mammalian development.
During vertebrate development, spontaneous pattern formation (formation of pattern out of seemingly homogeneous initial state) is frequently observed, such as lung branching, limb skeletogenesis and skull suture interdigitation. These processes are quite complex and we cannot understand them by simply analyzing each gene involved. We formulated mathematical models which represents essential feature of these pattern formation process, and are now trying to verify the models by developing novel experimental methods.


Anatomy and Developmental Biology
Associate
　Professor
：
Takashi Miura
Assistant
　Professor
：
Junko Okano
TEL ： +81-75-753-4341
FAX ： +81-75-751-7529
e-mail ： miura-takashiumin.net
URL ： http://www.anat1.med.kyoto-u.ac.jp
The reporter worm (C. elegans) depict that three different splicing isoforms are generated in pharynx (blue), intestine (green), or neuron (red).
The reporter cells visualize the alternative selection of splicing isoforms in different cell lines.
The reporter mice allows analyses of tissue specific alternative splicing mechanism in a whole body level.
We invented novel small chemical compounds that manipulate alternative splicing selections.
Recent Publications
1. Ohno, G., Hagiwara, M., and Kuroyanagi, H. (2008) STAR family RNA-binding protein ASD-2 regulates developmental switching of mutually exclusive alternative splicing in vivo. Genes & Dev., 22, 360-374.
2. Kuroyanagi, H., Kobayashi, T., Mitani, S., and Hagiwara, M. (2006) A transgenic reporter reveals cell-type-specific expression profiles and regulation mechanisms of alternatively-spliced exons in vivo. Nature Methods 3, 909-915.
3. Ideue T, Sasaki Y, Hagiwara M and Hirose T. (2007) Introns play an essential role in splicing-dependent formation of the exon junction complex. Genes & Dev., 21, 1993-1998.
4. Hirose T., Ideue, T., Nagai, M., Hagiwara, M., Shu, M., and Steitz, J.A. (2006) A spliceosomal intron-binding protein, IBP160, links position-dependent assembly of intorn-encoded box C/C snoRNP to pre-mRNA splicing. Mol. Cell 23,673-684.
5. Fukuhara T, Hosoya T, Shimizu S, Sumi K, Oshiro T, Yoshinaka Y, Suzuki M, Yamamoto N, Herzenberg LA, Herzenberg LA and Hagiwara M (2006) Utilization of host SR protein kinases and RNA-splicing machinery during viral replication. Proc Natl Acad Sci USA. 103(30):11329-11333.
6. Miura T, Hartmann D, Kinboshi M, Komada M, Ishibashi M, Shiota K, The cyst-branch difference in developing chick lung results from a different morphogen diffusion coefficient, Mech. Dev. 126, 160-72 (2009)