Dataset Information

Hearing impairment and associated morphological changes in pituitary adenylate cyclase activating polypeptide (PACAP)-deficient mice.

ABSTRACT: Pituitary adenylate cyclase activating polypeptide (PACAP) is a regulatory and cytoprotective neuropeptide, its deficiency implies accelerated aging in mice. It is present in the auditory system having antiapoptotic effects. Expression of Ca²⁺-binding proteins and its PAC1 receptor differs in the inner ear of PACAP-deficient (KO) and wild-type (WT) mice. Our aim was to elucidate the functional role of PACAP in the auditory system. Auditory brainstem response (ABR) tests found higher hearing thresholds in KO mice at click and low frequency burst stimuli. Hearing impairment at higher frequencies showed as reduced ABR wave amplitudes and latencies in KO animals. Increase in neuronal activity, demonstrated by c-Fos immunolabeling, was lower in KO mice after noise exposure in the ventral and dorsal cochlear nuclei. Noise induced neuronal activation was similar in further relay nuclei of the auditory pathway of WT and KO mice. Based on the similar inflammatory and angiogenic protein profile data from cochlear duct lysates, neither inflammation nor disturbed angiogenesis, as potential pathological components in sensorineural hearing losses, seem to be involved in the pathomechanism of the presented functional and morphological changes in PACAP KO mice. The hearing impairment is probably concomitant with the markedly accelerated aging processes in these animals.

SUBMITTER: Fulop DB

PROVIDER: S-EPMC6787024 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Hearing impairment and associated morphological changes in pituitary adenylate cyclase activating polypeptide (PACAP)-deficient mice.

Fulop Daniel Balazs DB Humli Viktoria V Szepesy Judit J Ott Virag V Reglodi Dora D Gaszner Balazs B Nemeth Adrienn A Szirmai Agnes A Tamas Laszlo L Hashimoto Hitoshi H Zelles Tibor T Tamas Andrea A

Scientific reports 20191010 1

Pituitary adenylate cyclase activating polypeptide (PACAP) is a regulatory and cytoprotective neuropeptide, its deficiency implies accelerated aging in mice. It is present in the auditory system having antiapoptotic effects. Expression of Ca<sup>2+</sup>-binding proteins and its PAC1 receptor differs in the inner ear of PACAP-deficient (KO) and wild-type (WT) mice. Our aim was to elucidate the functional role of PACAP in the auditory system. Auditory brainstem response (ABR) tests found higher h ...[more]

PMID: 31601840

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Project description:Pituitary adenylate cyclase activating polypeptide (PACAP) is a well-conserved neuropeptide characteristic of vertebrates. This pluripotent hypothalamic neuropeptide regulates neurotransmitter release, intestinal motility, metabolism, cell division/differentiation, and immunity. In vertebrates, PACAP has a specific receptor (PAC1) but it can also activate the Vasoactive Intestinal Peptide receptors (VPAC1 and VPAC2). The evolution of the vertebrate PACAP ligand - receptor pair has been well-described. In contrast, the situation in invertebrates is much less clear. The PACAP ligand - receptor pair in invertebrates has mainly been studied using heterologous antibodies raised against mammalian peptides. A few partial PACAP cDNA clones sharing >87% aa identity with vertebrate PACAP have been isolated from a cnidarian, several protostomes and tunicates but no gene has been reported. Moreover, current evolutionary models of the peptide and receptors using molecular data from phylogenetically distinct invertebrate species (mostly nematodes and arthropods) suggests the PACAP ligand and receptors are exclusive to vertebrate genomes. A basal deuterostome, the cephalochordate amphioxus (Branchiostoma floridae), is the only invertebrate in which elements of a PACAP-like system exists but the peptides and receptor share relatively low sequence conservation with the vertebrate homolog system and are a hybrid with the vertebrate glucagon system. In this study, the evolution of the PACAP system is revisited taking advantage of the burgeoning sequence data (genome and transcriptomes) available for invertebrates to uncover clues about when it first appeared. The results suggest that elements of the PACAP system are absent from protozoans, non-bilaterians, and protostomes and they only emerged after the protostome-deuterostome divergence. PACAP and its receptors appeared in vertebrate genomes and they probably shared a common ancestral origin with the cephalochordate PACAP/GCG-like system which after the genome tetraploidization events that preceded the vertebrate radiation generated the PACAP ligand and receptor pair and also the other members of the Secretin family peptides and their receptors.

Project description:Pituitary adenylate cyclase-activating polypeptide (PACAP) promotes neurite outgrowth and inhibits proliferation of rat pheochromocytoma (PC12) cells. Characterizing the PACAP-differentiated PC12 cell transcriptome should provide genetic insight into how these processes occur in these cells, and in neuronal precursors in vivo. For this purpose, RNA samples were collected from PC12 cells before or after a 6-h treatment with PACAP, from which a labeled cDNA was hybridized to a high-density cDNA array containing 15 365 genes. The genomic response to PACAP involves at least 73 genes. Among the genes differentially expressed in the presence of PACAP, 71% were up regulated, and 29% down regulated, 2-fold or more. Sixty-six percent of the messages affected by PACAP code for functionally categorized proteins, most not previously known to be regulated during PC12 cell differentiation. PACAP has been shown to induce PC12 cell neurite outgrowth through the mitogen-activated protein kinase kinase (MEK) pathway independently of protein kinase A (PKA). Therefore treatments were conducted in the absence or presence of the PKA inhibitor H89, or the MEK inhibitor U0126 in order to identify subsets of genes involved in specific aspects of PC12 cell differentiation. Co-treatment of PC12 cells with PACAP plus H89 revealed a cluster of five genes specifically regulated through the PKA pathway and co-treatment of the cells with PACAP and U0126 revealed a cluster of 13 messages specifically activated through the MEK pathway. Many of the known genes regulated by PACAP have been associated with neuritogenesis (i.e. villin 2 or annexin A2) or cell growth (i.e. growth arrest specific 1 or cyclin B2). Thus, some of the expressed sequence tags (ESTs) that exhibit the same regulation pattern (i.e. AU016391 or AW552690) may also be involved in the neuritogenic and anti-mitogenic effects of PACAP in PC12 cells. Among the 73 PACAP regulated genes, 10 are disqualified on pharmacological grounds as actors in PACAP-mediated neurite outgrowth or growth arrest, leaving 63 new PACAP-regulated genes implicated in neuronal differentiation. Thirteen of these are candidates for mediating ERK-dependent neurite outgrowth, and 47 are possibly involved in the ERK-independent growth arrest induced by PACAP.

Dataset Information

Hearing impairment and associated morphological changes in pituitary adenylate cyclase activating polypeptide (PACAP)-deficient mice.

Publications

Hearing impairment and associated morphological changes in pituitary adenylate cyclase activating polypeptide (PACAP)-deficient mice.

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