FAM19A5 is a secretory protein that is predominantly expressed in the brain. Although the FAM19A5 gene has been found to be associated with neurological and/or psychiatric diseases, only limited information is available on its function in the brain. Using FAM19A5-LacZ knock-in mice, we determined the expression pattern of FAM19A5 in developing and adult brains and identified cell types that express FAM19A5 in naïve and traumatic brain injury (TBI)–induced brains. According to X-gal staining results, FAM19A5 is expressed in the ventricular zone and ganglionic eminence at a very early stage of brain development, suggesting its functions are related to the generation of neural stem cells and oligodendrocyte precursor cells (OPCs). In the later stages of developing embryos and in adult mice, FAM19A5 expression expanded broadly to particular regions of the brain, including layers 2/3 and 5 of the cortex, cornu amonis (CA) region of the hippocampus, and the corpus callosum. X-gal staining combined with immunostaining for a variety of cell-type markers revealed that FAM19A5 is expressed in many different cell types, including neurons, OPCs, astrocytes, and microglia; however, only some populations of these cell types produce FAM19A5. In a subpopulation of neuronal cells, TBI led to increased X-gal staining that extended to the nucleus, marked by slightly condensed content and increased heterochromatin formation along the nuclear border. Similarly, nuclear extension of X-gal staining occurred in a subpopulation of OPCs in the corpus callosum of the TBI-induced brain. Together, these results suggest that FAM19A5 plays a role in nervous system development from an early stage and increases its expression in response to pathological conditions in subsets of neurons and OPCs of the adult brain.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease (PD), but the pathogenic mechanism underlying LRRK2 mutations remains unresolved. In this study, we investigate the consequence of inactivation of LRRK2 and its functional homolog LRRK1 in male and female mice up to 25 months of age using behavioral, neurochemical, neuropathological, and ultrastructural analyses. We report that LRRK1 and LRRK2 double knock-out (LRRK DKO) mice exhibit impaired motor coordination at 12 months of age before the onset of dopaminergic neuron loss in the substantia nigra (SNpc). Moreover, LRRK DKO mice develop age-dependent, progressive loss of dopaminergic terminals in the striatum. Evoked dopamine (DA) release measured by fast-scan cyclic voltammetry in the dorsal striatum is also reduced in the absence of LRRK. Furthermore, LRRK DKO mice at 20-25 months of age show substantial loss of dopaminergic neurons in the SNpc. The surviving SNpc neurons in LRRK DKO mice at 25 months of age accumulate large numbers of autophagic and autolysosomal vacuoles and are accompanied with microgliosis. Surprisingly, the cerebral cortex is unaffected, as shown by normal cortical volume and neuron number as well as unchanged number of apoptotic cells and microglia in LRRK DKO mice at 25 months. These findings show that loss of LRRK function causes impairments in motor coordination, degeneration of dopaminergic terminals, reduction of evoked DA release, and selective loss of dopaminergic neurons in the SNpc, indicating that LRRK DKO mice are unique models for better understanding dopaminergic neurodegeneration in PD.

FAM19A5 (also called TAFA5) is a novel secretory protein that is primarily expressed in the brain. However, a recent study reported that FAM19A5 is an adipocyte-derived adipokine that regulates vascular smooth muscle function. Furthermore, genome-wide association study (GWAS) and RNA-seq analyses revealed that the FAM19A5 was associated with a variety of diseases and tumorigenesis in peripheral tissues. We investigated FAM19A5 transcript and protein levels in the FAM19A5 peripheral expression 2 peripheral tissues, including adipose tissues from wild-type, FAM19A5 knock-out, and LacZ knock-in mice. In general, total FAM19A5 transcript levels in the central and peripheral nervous systems were higher than levels in any of the peripheral tissues including adipose tissues. Brain tissues expressed similar levels of the FAM19A5 transcript isoforms 1 and 2, whereas expression in the peripheral tissues predominantly expressed isoform 2. In the peripheral tissues, but not the brain, FAM19A5 protein levels in adipose and reproductive tissues were below detectable limits for analysis by Western blot. Additionally, we found that FAM19A5 protein did not interact with the S1PR2 receptor for G-protein-mediated signal transduction, β-arrestin recruitment, and ligandmediated internalization. Instead, FAM19A5 was internalized into HEK293 cells in an extracellular matrix protein-dependent manner. Taken together, the present study determined basal levels of FAM19A5 transcripts and proteins in peripheral tissues, which provides compelling evidence to further investigate the function of FAM19A5 in peripheral tissues under pathological conditions, including metabolic diseases and/or tumorigenesis.

Family with sequence similarity 19 (chemokine (C-C motif)-like), member A5 (FAM19A5) is a chemokine-like secretory protein recently identified to be involved in the regulation of osteoclast formation, post-injury neointima formation, and depression. Here, we identified FAM19A5l, an orthologous zebrafish gene that originated from a common ancestral FAM19A5 gene. FAM19A5l was expressed in trigeminal and dorsal root ganglion neurons as well as distinct neuronal subsets of the central nervous system of zebrafish. Interestingly, FAM19A5l + trigeminal neurons were nociceptors that co-localized with TRPA1b and TRPV1, and responded to mustard-oil treatment. Behavioral analysis revealed that the nociceptive response to mustard oil decreased in FAM19A5l-knockout zebrafish larvae. In addition, TRPA1b and NGFa mRNA levels were down-and up-regulated in FAM19A5l-knockout andoverexpressing transgenic zebrafish, respectively. Together, our data suggested that FAM19A5l played a role in nociceptive responses to mustard oil by regulating TRPA1b and NGFa expression in zebrafish.

SUMMARYFamily with sequence similarity 19 (chemokine (C-C motif)-like), member A5 (FAM19A5) is a chemokine-like secretory protein recently identified to be involved in the regulation of osteoclast formation, post-injury neointima formation, and depression. Here, we identified FAM19A5l, an orthologous zebrafish gene that originated from a common ancestral FAM19A5 gene. FAM19A5l was expressed in trigeminal and dorsal root ganglion neurons as well as distinct neuronal subsets of the central nervous system of zebrafish. Interestingly, FAM19A5l+ trigeminal neurons were nociceptors that co-localized with TRPA1b and TRPV1, and responded to mustard-oil treatment. Behavioral analysis revealed that the nociceptive response to mustard oil decreased in FAM19A5l-knockout zebrafish larvae. In addition, TRPA1b and NGFa mRNA levels were down- and up-regulated in FAM19A5l-knockout and - overexpressing transgenic zebrafish, respectively. Together, our data suggested that FAM19A5l played a role in nociceptive responses to mustard oil by regulating TRPA1b and NGFa expression in zebrafish.

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