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 6

Hap1 reduces lysosomal degradation of TrkB.

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Hap1 reduces lysosomal degradation of TrkB. (A) Western blot analysis of...
(A) Western blot analysis of degradation of TrkB in the presence of Hap1A in transfected HEK293 cells that were treated without or with BDNF (100 ng/ml). (B) Fluorescent images of transfected cells expressing TrkB-GFP after BDNF treatment in the absence or presence of Hap1A. Quantification data are also present beneath A (n = 3) and B (n = 8). Scale bar: 10 μm. (C) Lysosome fractions isolated from the hypothalamic regions in WT and Hap1-KO mice showing a decreased level of TrkB in the absence of Hap1. Blots were probed with antibodies to the lysosome protein, Lamp1, Hap1, TrkB, and tubulin. The relative level of TrkB (lysosome to total, n = 6) was quantified. *P < 0.05. (D) Degradation of transfected TrkB is reduced by the lysosome enzyme inhibitors leupeptin/pepstatin (10 μg/ml), but not the proteasome inhibitor lacacystin (10 μM). DMSO served as a control. (E) Quantification of the ratio of TrkB to tubulin (n = 3) is shown. **P < 0.01. All error bars represent SEM.