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 3

Lack of Hap1 does not affect astrocyte differentiation in the mouse neurospheres.

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Lack of Hap1 does not affect astrocyte differentiation in the mouse neur...
(A) Low-magnification micrograph (×10) showing that neurospheres from WT mouse brain express Hap1 (red) and nestin (green). The cellular nuclei were labeled by Hoechst dye (blue). Scale bar: 20 μm. (B) High-magnification micrograph (×40) showing the coexpression of β-tubulin III (green) and Hap1 (red) in differentiated neuronal cells in the neurospheres. Scale bar: 10 μm. (C) Immunostaining of the mouse neurospheres, which had been differentiated for 5 days in culture, with antibodies to the neuronal protein β-tubulin III and glial protein GFAP (upper panel). Scale bar: 40 μm. (D) The relative numbers of neuronal (β-tubulin III–positive) cells were counted at different time points after induction with retinoic acid and 2% serum (lower panel). Note that there are more neuronal cells in WT and Het groups than in the KO group. In each group, the value represents mean ± SD obtained from 20 neurospheres from each group. *P < 0.05; **P < 0.01; ***P < 0.001 compared with Hap1-KO neurospheres. (E) Western blot analysis of cultured NSC, aNSCs, and mature astrocytes showing the absence of Hap1 in the mature glial cells. (F) Western blots of WT and Hap1-null (KO) mouse hypothalamus showing that the absence of Hap1 does not affect the level of GFAP. Two different samples of each genotype were analyzed via Western blotting.