The role of Huntingtin-associated protein 1 (Hap1) in postnatal development Open Access

Xiang, Jianxing (2014)

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Huntingtin-associated protein 1 (Hap1) is an intriguing neuronal-enriched protein that interacts with several disease-causing proteins such as huntingtin (htt) and Ahi1, whose mutations lead to Huntington's disease (HD) and Joubert syndrome (JS), respectively. As Hap1 might be involved in the pathogenesis of both neurodegenerative and neurodevelopmental disorders, as HD and JS represent, a systematic study of the role of Hap1 at different ages could considerably help us unravel the mechanisms of a number of diseases as well as develop novel therapies. To achieve that, we generated an inducible Hap1 knockout (KO) mouse model in which Hap1 can be deleted via tamoxifen (TM) injection at different ages. By inducing Hap1 KO at early postnatal days, we observed growth retardation, a phenotype that is similar to that of germline Hap1 KO mice, and was not seen when Hap1 was depleted at postnatal day 21 (P21) or later. To look for possible mechanisms, we examined neurogenesis in the hypothalamus, a brain region critical for food intake and energy expenditure, and found that it was also impaired in early Hap1 KO mice. Moreover, tropomyosin-related kinase B (TrkB), a receptor for brain-derived neurotrophic factor (BDNF) is downregulated by the loss of Hap1, and acute treatment of BDNF in the ventricles of Hap1 KO mice rescued the impaired hypothalamic neurogenesis, indicating that BDNF/TrkB signaling, which is suppressed in the absence of Hap1, is critical for postnatal hypothalamic neurogenesis. Interestingly, early, but not late postnatal Hap1 KO mice when grown to adults exhibited depressive behavior, which was accompanied by the reduction of neurogenesis in the hippocampal dentate gyrus. Adult expressed Hap1, however, protects mice from stress induced depressive behavior by maintaining adult hippocampal neurogenesis. Together, these results reveal differential roles of Hap1 at different postnatal stages, and suggest that Hap1 is required for postnatal neurogenesis, a mechanism that may underlie the growth defect of Hap1 KO mice, and could contribute to the pathogenesis of a number of neurological diseases such as depression. The role of Hap1 in stress response could also have profound influence on the progression of certain diseases.

Table of Contents

Chapter 1: General Introduction

1.1 Huntingtin-associated protein 1 (Hap1) 2

1.2 Hap1 in molecular trafficking 4

1.3 Animal models of Hap1 KO 8

1.4 Hap1 and HD 11

1.5 Hap1 and other neurological diseases 14

1.6 Dissertation goals 20

Chapter 2: Essential role of Hap1 in mouse early postnatal survival

and growth

Abstract 24

Introduction 24

Results 26

Discussion 28

Materials and Methods 31

Chapter 3: Hap1 regulates postnatal neurogenesis and neurotrophin

receptor sortingAbstract 41

Introduction 41

Results 44

Discussion 51

Materials and Methods 55

Chapter 4: Differential roles of early postnatal and later stage Hap1

expression in hippocampal neurogenesis and depression

Abstract 95

Introduction 95

Results 98

Discussion 103

Materials and Methods 106

Chapter 5: General conclusions and future directions

General conclusions 124

Future directions 131

References 144

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