Life science
Healthcare, Drug discovery

Function of a gene involved in polarized transport andapplication to the therapy for human diseases
Department of Cell Biology, Graduate School of Medicine
Assistant Professor Masataka Kunii

Researchmap https://researchmap.jp/kunimasa

Professor Akihiro Harada

Researchmap https://researchmap.jp/aharadaLife science

Abstract
In polarized cells such as epithelial cells and neurons, newly
synthesized proteins are transported to distinct parts of the cellsurfaces by polarized transport machinery. Transport vesicles
containing proteins fuse with the plasma membrane via the facilitation of SNARE proteins. SNAP23 is one of the SNARE proteins
and is involved in exocytotic events in diverse cells. However, thein vivo function of SNAP23 remains largely unknown. Recently, wegenerated some tissue-specific Snap23 knockout (KO) mice. The
loss of SNAP23 in the exocrine and endocrine pancreas resulted indecreased and increased fusion of granules to the plasma membrane, respectively. These results demonstrate opposing roles for
SNAP23 in the secretion mechanisms of the endocrine and exocrine pancreas. Furthermore, we identified a low-molecular-weightcompound, MF286, which binds specifically to SNAP23 and promotes insulin secretion in mice. Additionally, the central nervous
system-specific ablation of SNAP23 results in mice with severe
hypoplasia of the neocortex and no cerebellum, suggesting that
SNAP23 is necessary for the brain development.

▍ Significance of the research and Future perspective
Our KO studies revealed the different functions of SNAP23 in
the pancreas and brain. SNAP23-inhibitor MF286 promotes insulin
secretion and improved glucose tolerance in mice, suggestingMF286 may be a candidate drug for diabetes. Furthermore, ourfindings may have a potential to elucidate the pathogenesis ofhuman brain disorders such as hydrocephalus, spina bifida, andDandy-Walker syndrome.

▍ Background & Results
Cell polarity is essential for the generation of our tissues andtheir physiological functions. In the polarized cells such as epithelial cells and neurons, newly synthesized secretory or membraneproteins are transported to distinct parts (apical and basolateralin epithelial cells or axon and dendrite in neurons) of the cell surfaces by polarized transport machinery. Transport vesicles containing proteins fuse with the plasma membrane via the facilitationof SNARE proteins. In humans, 38 SNARE proteins have been
identified. Each SNARE protein exhibits distinct tissue expression
and intracellular localization as well as complex formation with its
appropriate partners. SNAP23 is one of the SNARE proteins andis involved in exocytotic events in diverse cells. However, the invivo function of SNAP23 in polarized transport remains largely
unknown. To know the in vivo function of SNAP23, we generated
some tissue-specific Snap23 KO mice. The exocrine-specific KOmice showed decreased fusion of zymogen granules, but the endocrine-specific KO mice showed increased fusion of insulin granules and improved glucose tolerance. These results suggest thatSNAP23 plays opposite roles in secretion in the exocrine and endocrine pancreas. Furthermore, we found that the SNAP23-binding
compound MF286 promoted insulin secretion and improved glucose tolerance in mice. Additionally, loss of SNAP23 in the central
nervous system results in severe hypoplasia of the cerebral cortex
and lacked a hippocampus and cerebellum. We found that SNARE
complex composed of SNAP23, VAMP8, and Stx1B mediates thelocalization of N-cadherin to the apical plasma membrane and is
crucial for the polarization of neural progenitor cells in the developing brain.

Fig.1 Inhibitory role of SNAP23 for insulin secretion in the pancreatic β cells.

Fig.2. Function of SNAP23 for polarization of the neural progenitor cells.

P a t e n t Japanese Patent Application No.2017-068871, Japanese Unexamined Patent Publication No.2018-168132
Kunii, Masataka; Ohara-Imaizumi, Mica; Takahashi, Noriko et al. Opposing roles for SNAP23 in secretion in exocrine and endocrine pancreatic cells. J CellBiol. 2016 Oct 10;215(1):121-138. doi: 10.1083/jcb.201604030.
Tr e a t i s eKunii, Masataka; Noguchi, Yuria; Yoshimura, Shin-ichiro et al. SNAP23 deficiency causes severe brain dysplasia through the loss of radial glial cell polarity.
J Cell Biol. 2021 Jan 4;220(1):e201910080. doi: 10.1083/jcb.201910080.
UR
L https://www.harada-lab.online/
K e y w o r d cell polarity, polarized transport, SNAP23, insulin secretion, neurodevelopment