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Life Sci. 2019 Apr 15;223:54-61. doi: 10.1016/j.lfs.2019.03.023. Epub 2019 Mar 11.

Sema3A - mediated modulation of NR1D1 expression may be involved in the regulation of axonal guidance signaling by the microbiota.

Author information

1
Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Institute of Neuroscience, Chongqing Medical University, Chongqing, China,; Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, China.
2
Ning Xia Medical University, 750004, NO804, Road Shengli, Yinchuan, Ningxia, China.
3
Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, China; School of Public Health and Management, Chongqing Medical University, Chongqing, China.
4
Department of Laboratory Animal Science, College of Basic Medical Sciences, Third Military Medical University, Chongqing, China.
5
Institute of Life Sciences, Chongqing Medical University, Chongqing, China.
6
Department of Nephrology, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
7
Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
8
Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing, China; Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, China.
9
Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, China.
10
Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing, China.
11
Department of Laboratory Animal Science, College of Basic Medical Sciences, Third Military Medical University, Chongqing, China. Electronic address: weihong63528@163.com.
12
Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing, China; Institute of Neuroscience, Chongqing Medical University, Chongqing, China,; Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, China. Electronic address: xiepeng@cqmu.edu.cn.

Abstract

AIMS:

The microbiota has a profound impact on host development and function. Axon guidance is essential for the formation of neural circuits and plays an important role in neurological diseases and behavioral disorders. However, the impact of the microbiota on axon guidance signaling is unclear.

MAIN METHODS:

Gnotobiotic models-germ free mice were applied to explore behavioral phenotypes and possible molecular mechanisms that were evaluated by Realtime-PCR and western blot analysis. Primary cultures of mouse cortical neurons were performed to demonstrate the role of Sema3A on NR1D1 expression.

KEY FINDINGS:

The results showed that the microbiota modulates host behavior, and that colonization is not sufficient to normalize behavioral alterations in germ-free (GF) mice. Five genes, Sema3A, Sema3E, EphB2, Slit3 and Robo1, were differentially expressed in GF and specific pathogen-free (SPF) mice. Furthermore, colonization did not completely reverse the differential expression, which was consistent with the behavioral phenotypes in colonization germ-free (CGF) mice. The transcript and protein levels of Sema3A, and of its membrane-bound co-receptor NRP1, were increased in GF mice. Interestingly, Sema3A inhibited the expression of NR1D1, which was blocked by a RhoA/ROCK pathway agonist in primary cortical neurons. The NR1D1 and ROCK2 expression levels were reduced in GF and CGF mice compared with SPF mice, consistent with the increased expression of Sema3A.

SIGNIFICANCE:

Our findings suggest that the microbiota regulates axon guidance signaling in the prefrontal cortex. Furthermore, this effect appears to involve the inhibition of NR1D1 expression by Sema3A through the RhoA/ROCK pathway.

KEYWORDS:

Axon guidance signaling; Microbiota; NR1D1; RhoA/ROCK pathway; Sema3A

PMID:
30872177
DOI:
10.1016/j.lfs.2019.03.023
[Indexed for MEDLINE]

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