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

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 1

Generation of conditional Hap1-KO mice.

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Generation of conditional Hap1-KO mice. (A) Western blot analysis of H...
(A) Western blot analysis of Hap1 expression in developing and adult WT mouse brains. Ctx, cortex; Hypo, hypothalamus. The lanes were run on the same gel but were noncontiguous. (B) The exon 1 of the mouse Hap1 gene was flanked by loxP sites and the neomycin-resistant (neo) gene for generating floxed Hap1 mice. The floxed Hap1 mice were crossed with transgenic mice expressing Cre-ER, resulting in disruption of the Hap1 gene. (C) Western blot analysis of the whole-brain tissues of WT and homozygous (KO) floxed Hap1 mice 15 days after TM injection at P1. The brain tissues from germline KO and heterozygous mice (het) were also included. (D) Western blots of brain regional tissues of Hap1 adult KO mice. The brain tissues of 3-month-old mice were isolated 10 days after TM injection. Note that Hap1 consists of 2 isoforms (Hap1A and Hap1B) and is markedly reduced in homozygous (KO) floxed Hap1 mouse brain as compared with Het mouse brain. (E) Reduced body size of Hap1 P1 KO mice 15 days after TM injection at P1 compared with a WT mouse that had also been injected with TM.