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 7

Hap1 stabilizes sortilin association with TrkB and promotes TrkB transport.

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Hap1 stabilizes sortilin association with TrkB and promotes TrkB transpo...
(A) Immunoprecipitation of endogenous sortilin in HEK293 cells showing the coprecipitation of transfected TrkB and Hap1A. (B) Coexpression of Hap1A increased the association of TrkB with sortilin after cells were treated with BDNF (100 ng/ml for 30 minutes). The lanes were run on the same gel but were not contiguous. The ratio of precipitated to input (IP/input) is shown in the right panel (n = 3). (C) Immunoprecipitation of TrkB from the hypothalamic tissues of WT or Hap1 P1 KO mice showing a reduced precipitation of sortilin when Hap1 is absent. The ratios of precipitated sortilin to TrkB are also presented (n = 3, right panel). *P < 0.05. (D) Immunoprecipitation of TrkB from P1 KO mouse hypothalamic tissues showing reduced association of sortilin and kinesin with TrkB. In B and D, IP/input is normalized to control (n = 3). *P < 0.05; **P < 0.01. (E) Loss of Hap1 reduces the anterograde transport of TrkB in cultured olfactory neuronal cells at DIV4. The neuronal tips were photobleached and then examined for the recovery of TrkB-GFP levels, which represent the anterograde transport of TrkB-GFP from the cell body to neurite tips. Arrows indicate anterograde transport directions. Scale bar: 5 μm. (F) Quantitation of anterograde and retrograde transport of TrkB-GFP in cultured WT and KO neurons via FRAP. For studying anterograde (WT = 9, KO = 10) and retrograde (WT = 7, KO = 9) trafficking of TrkB, fluorescence in neurites near tips and soma was photobleached, respectively. All error bars represent SEM.