Neuroanatomical distribution of huntingtin‐associated protein 1‐mRNA in the male mouse brain

Abstract

Huntingtin-associated protein 1 (HAP1) was identified as an interactor of the gene product (Huntingtin) responsible for Huntington's disease and found to be a core component of the stigmoid body. Even though HAP1 is highly expressed in the brain, detailed information on HAP1 distribution has not been fully described. Focusing on the neuroanatomical analysis of HAP1-mRNA expression using in situ hybridization histochemistry, the present study clarified its detailed regional distribution in the entire mouse brain. Mouse HAP1 (Hap1)-mRNAs were abundantly expressed in the limbic-related forebrain regions and midline/periventricular brainstem regions including the olfactory bulb, limbic-associated cortices, hippocampus, septum, amygdala, bed nucleus of the stria terminalis, preoptico-hypothalamic regions, central gray, raphe nuclei, locus coeruleus, parabrachial nuclei, nucleus of the solitary tract, and area postrema. In contrast, little expression was detected in the striatum and thalamus, implying that Hap1 is associated with neurodegeneration-sparing regions rather than target lesions in Huntington's disease. The distribution pattern, resembling that of the stigmoid body, suggests that HAP1 and the stigmoid body are implicated in protection from neuronal death rather than induction of neurodegeneration in Huntington's disease, and that they play an important role in integrating instinct behaviors and underlying autonomic, visceral, arousal, drive, memory, and neuroendocrinergic functions, particularly during extensive homeostatic or emotional processes. These data will provide an important morphological base for a future understanding of functions of HAP1 and the stigmoid body in the brain.

Immunohistochemical Localization of Huntingtin-associated Protein 1 in Endocrine System of the Rat

“…By double-labeling immunofluorescence, we have found that the neurons in both supraoptic and paraventricular nuclei express HAP1, which colocalized with vasopressin (Shen et al, unpublished data). HAP1 has been regarded as an essential component and molecular marker of the stigmoid body (Gutekunst et al 1998;Fujinaga et al 2004). The presence of HAP1-immunoreactive stigmoid bodies in the endocrine cells also supports the idea that HAP1 is expressed in these cells.…”

Anti-human placental antigen complex X-P2 (hPAX-P2) anti-serum recognizes C-terminus of huntingtin-associated protein 1A common to 1B as a determinant marker for the stigmoid body

“…Therefore, it appears possible that the XP2S domain of HAP1 isoforms (recognition site for the anti-hPAX-P2 anti-serum) is exposed in the STB-like inclusion, whereas some indeterminate cytoplasmic interactors might conceal the XP2S domain when HAP1 is diVusely expressed in cytoplasm (particularly in case of HAP1B). Although HAP1B-speciWc interactor has yet to be reported, many HAP1 binding partners have been identiWed in vitro (see Fujinaga et al 2004;Li and Li 2005;Rong et al 2007a). In particular, since the binding regions for GABA A R (amino acids 220-520 in HAP1) (Kittler et al 2004), kinesin light chain (KLC) (446-599 in HAP1) , inositol (1, 4, 5)-triphosphate (InsP 3 ) receptor type I (InsP 3 R1) (273-599 in HAP1) (Tang et al 2003(Tang et al , 2004) and 14-3-3 isoforms (441-599 in HAP1) (Rong et al 2007b) overlap the XP2S domain in HAP1 474-577 , it appears possible that they might conceal or modify the HAP1-XP2S domain in cytoplasm and hamper the recognition by anti-hPAX-P2 anti-serum.…”

“…In addition, the transfection of HAP1-cDNA into HEK293 cells induces the formation of large cytoplasmic STB-like inclusions in vitro (Li et al 1998a, b, c). Histological studies using immunohistochemistry (Li et al 2003) or in situ hybridization (Page et al 1998;Dragatsis et al 2000;Fujinaga et al 2004) clariWed that HAP1-protein and-mRNA are prominently expressed in the limbic, hypothalamic, mid-brain, and lower brainstem mid-line regions and that the distribution is compatible with that of the STB in the rodent brain. It has recently been reported that the emergence of HAP1/STB inclusions were inhibited in Hap1 (+/¡)-mice (Chan et al 2002).…”

“…Hap1 (¡/¡)-mice showed hypothalamic neuronal cell death (Li et al 2003) and dysfunction of early postnatal feeding behavior (Chan et al 2002;Dragatsis et al 2004), which is associated with the expression level of -aminobutyric acid type A receptor (GABA A R) . Regarding its involvement in HD, HAP1/STB has been speculated to play a protective role against neurodegeneration in HD (Kamei et al 2001;Koga et al 2002;Li et al 2003;Fujinaga et al 2004). We recently also demonstrated that the co-transfection of cDNAs of HAP1 and androgen receptor (AR) in HEp-2 cells induces prominent STB-like inclusions sequestering AR and that HAP1 expression suppresses apoptosis induced by polyglutamine-expanded AR derived from spinal and bulbar muscular atrophy (SBMA) (Takeshita et al 2006).…”

Huntingtin associated protein 1 and its functions

“…[94][95][96] HAP1 is a core component of the SBs and important for fetal and early postnatal neural development, particularly in the hypothalamic or limbic networks and HAP1/SBs has been assumed to play a protective role against neurodegeneration in HD. 96,99 Whether HAP1 plays any role in the pathological protein aggregation such as in Alzheimer disease, Parkinson disease and Huntington disease is not clear.…”