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Huntingtin-associated protein 1 regulates postnatal neurogenesis and neurotrophin receptor sorting
Jianxing Xiang, … , Shi-Hua Li, Xiao-Jiang Li
Jianxing Xiang, … , Shi-Hua Li, Xiao-Jiang Li
Published December 20, 2013
Citation Information: J Clin Invest. 2014;124(1):85-98. https://doi.org/10.1172/JCI69206.
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Research Article Development

Huntingtin-associated protein 1 regulates postnatal neurogenesis and neurotrophin receptor sorting

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Abstract

Defective neurogenesis in the postnatal brain can lead to many neurological and psychiatric disorders, yet the mechanism behind postnatal neurogenesis remains to be investigated. Huntingtin-associated protein 1 (HAP1) participates in intracellular trafficking in neurons, and its absence leads to postnatal death in mice. Here, we used tamoxifen-induced (TM-induced) Cre recombination to deplete HAP1 in mice at different ages. We found that HAP1 reduction selectively affects survival and growth of postnatal mice, but not adults. Neurogenesis, but not gliogenesis, was affected in HAP1-null neurospheres and mouse brain. In the absence of HAP1, postnatal hypothalamic neurons exhibited reduced receptor tropomyosin-related kinase B (TRKB) levels and decreased survival. HAP1 stabilized the association of TRKB with the intracellular sorting protein sortilin, prevented TRKB degradation, and promoted its anterograde transport. Our findings indicate that intracellular sorting of neurotrophin receptors is critical for postnatal neurogenesis and could provide a therapeutic target for defective postnatal neurogenesis.

Authors

Jianxing Xiang, Hao Yang, Ting Zhao, Miao Sun, Xingshun Xu, Xin-Fu Zhou, Shi-Hua Li, Xiao-Jiang Li

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Figure 2

Reduced survival and growth of mice when Hap1-KO occurs at embryonic or early postnatal days.

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Reduced survival and growth of mice when Hap1-KO occurs at embryonic or ...
(A) The survival of Hap1-KO mice when the Hap1 gene is depleted from E11 in nestin-Cre Hap1-KO mice or from P1, P15, or P21 via TM injection. The control mice are heterozygous floxed Hap1 mice that had also been injected with TM. (B) Body weights of the control and Hap1-KO mice induced by TM at P1, P15, and P21. Arrows indicate the day when TM injections began. (C) Body weights of mice 10 days after TM injection at P1, P15, or P21. *P < 0.05; ***P < 0.001. The percentages of the control mouse body weight are also presented. Error bars represent SEM.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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