Targeted disruption of Huntingtin-associated protein-1 (Hap1) results in postnatal death due to depressed feeding behavior

Chan, Edmond Y W; Nasir, Jamal; Gutekunst, Claire Anne; Coleman, Sarah H.; Maclean, Alan; Maas, Alex; Metzler, Martina; Gertsenstein, Marina; Ross, Christopher A.; Nagy, András; Hayden, Michael R.

doi:10.1093/hmg/11.8.945

Cited by 75 publications

(58 citation statements)

References 44 publications

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“…The highest P/S ratio of Hap1 was seen in the hypothalamus (Fig. 1B), in agreement with the finding that SBs are more abundant in the hypothalamus than in other tissues (5,10,14). Thus, these results showed that the use of a detergent-based strategy to enrich SBs in mouse brain was feasible.…”

Section: Resultssupporting

confidence: 89%

“…DYRK1A is a major candidate gene for DS and likely is responsible for selective DS phenotypes. To look for DS symptoms that could be related to the regulation of DYRK1A on the Dcaf7-Hap1 interaction, we focused on growth retardation, which is a cardinal feature of DS (56) and is the most noticeable phenotype in Hap1-KO mice (5,10). Both individuals with DS and Hap1-KO mice exhibit impaired growth velocity after birth; the difference, however, is that in DS, growth velocity is most reduced between 6 mo and 3 y of age (56,57), whereas Hap1-KO mice are born at normal weight but display severe failure in body weight gain shortly after birth (5, 10).…”

Section: Discussionmentioning

confidence: 99%

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DYRK1A regulates Hap1–Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome

Xiang

Ning

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Huntingtin-associated protein 1 (Hap1) is known to be critical for postnatal hypothalamic function and growth. Hap1 forms stigmoid bodies (SBs), unique neuronal cytoplasmic inclusions of unknown function that are enriched in hypothalamic neurons. Here we developed a simple strategy to isolate the SB-enriched fraction from mouse brain. By analyzing Hap1 immunoprecipitants from this fraction, we identified a Hap1-interacting SB component, DDB1 and CUL4 associated factor 7 (Dcaf7)/WD40 repeat 68 (WDR68), whose protein level and nuclear translocation are regulated by Hap1. Moreover, we found that Hap1 bound Dcaf7 competitively in cytoplasm with dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), a protein implicated in Down syndrome (DS). Depleting Hap1 promoted the DYRK1A-Dcaf7 interaction and increased the DYRK1A protein level. Transgenic DS mice overexpressing DYRK1A showed reduced Hap1-Dcaf7 association in the hypothalamus. Furthermore, the overexpression of DYRK1A in the hypothalamus led to delayed growth in postnatal mice, suggesting that DYRK1A regulates the Hap1-Dcaf7 interaction and postnatal growth and that targeting Hap1 or Dcaf7 could ameliorate growth retardation in DS.H untingtin-associated protein 1 (Hap1) is a cytoplasmic protein highly expressed in neurons of the CNS (1, 2). Hap1 was initially recognized for its binding to polyglutamine-expanded huntingtin (Htt), the protein responsible for Huntington's disease (3). Because Hap1 is expressed at various levels in different types of neurons (1,(4)(5)(6)(7)(8), it is likely involved in cell type-specific functions of the brain. For example, Hap1 is abundantly expressed in the hypothalamus, and its expression in the hypothalamus influences the central control of feeding (9); as a direct result, mice lacking Hap1 are malnourished and die in the early postnatal period (5, 10, 11). The function of Hap1 is also age dependent and appears to be important for postnatal neurogenesis in the paraventricular nuclei, the lateral hypothalamus (5, 11), and the dentate gyrus of the hippocampus (7).The specific function of Hap1 in the hypothalamus may be associated with unique cytoplasmic structures called "stigmoid bodies" (SBs), which are formed by Hap1 in the hypothalamus (12, 13) and appear to be non-membrane-bound, ovoid to circular in shape, and 0.5-3 μm in diameter (14,15). Widely regarded as a determinant marker for SBs, Hap1 is capable of sequestering several important disease-related proteins into SB-like inclusions in cell cultures, including Abelson helper integration site 1 (Ahi1), androgen receptor, TBP, and ataxin-3 (6, 16-18). However, in vivo evidence for such sequestration exists only for Ahi1, which is responsible for specific forms of Joubert syndrome. Other proteins, such as SorLA/LR11, sortilin, 5-HT 7 receptor, and 14-3-3, are also reported to be associated with . Although SBs are abundant in the hypothalamus, their functions remain elusive, despite speculation that they might be involved in sex-steroid maturation (15). We bel...

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Section: Resultssupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

DYRK1A regulates Hap1–Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome

Xiang

Ning

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Huntingtin-associated protein 1 (Hap1), originally identified as a neuronal protein that interacts with the Huntington disease (HD) protein, huntingtin (htt), is critical for postnatal development, as Hap1-KO mice often die before P3 due to inhibited feeding behavior (2,3). Mounting evidence has shown that both htt and Hap1 participate in intracellular trafficking of membrane receptors (4,5).…”

Section: Introductionmentioning

confidence: 99%

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

Xiang¹,

Yang²,

Zhao³

et al. 2013

J. Clin. Invest.

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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.

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“…HAP1 interacts with the type 1 inositol (1,4,5)-triphosphate receptor (IP 3 R1), forming an IP 3 R1-HAP1A-htt ternary complex in which mutant htt enhances the sensitivity of IP 3 R1 to IP 3 (Tang et al, 2003). In addition, the critical role of HAP1 for neuronal function has been demonstrated in HAP1 knock-out mice, which show a feeding defect and postnatal death (Chan et al, 2002;Dragatsis et al, 2004) possibly attributable to the selective degeneration of hypothalamic neurons (Li et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Regulation of Intracellular Trafficking of Huntingtin-Associated Protein-1 Is Critical for TrkA Protein Levels and Neurite Outgrowth

Rong¹,

McGuire²,

Fang³

et al. 2006

J. Neurosci.

103

102

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Mutant huntingtin can affect vesicular and receptor trafficking via its abnormal protein interactions, suggesting that impairment of intracellular trafficking may contribute to Huntington's disease. There is growing evidence that huntingtin-associated protein-1 (HAP1) also interacts with microtubule-dependent transporters and is involved in intracellular trafficking. However, it remains unclear how the trafficking of HAP1 is regulated and contributes to neuronal function. Here we report that phosphorylation of HAP1 decreases its association with microtubule-dependent transport proteins dynactin p150 and kinesin light chain and reduces its localization in neurite tips. Suppressing HAP1 expression by RNA interference reduces neurite outgrowth and the level of tropomyosin-related kinase A receptor tyrosine kinase (TrkA), a nerve growth factor receptor whose internalization and trafficking are required for neurite outgrowth. HAP1 maintains the normal level of membrane TrkA by preventing the degradation of internalized TrkA. Mutant huntingtin also reduces the association of HAP1 with dynactin p150 and kinesin light chain and thereby decreases the intracellular level of TrkA. These findings suggest that HAP1 trafficking is critical for the stability of TrkA and neurite function, both of which can be attenuated by mutant huntingtin.

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Targeted disruption of Huntingtin-associated protein-1 (Hap1) results in postnatal death due to depressed feeding behavior

Cited by 75 publications

References 44 publications

DYRK1A regulates Hap1–Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome

DYRK1A regulates Hap1–Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome

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

Regulation of Intracellular Trafficking of Huntingtin-Associated Protein-1 Is Critical for TrkA Protein Levels and Neurite Outgrowth

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