In humans, the secretin-like G protein-coupled receptor (GPCR) family comprises 15 members with 18 corresponding peptide ligand genes. Although members have been identified in a large variety of vertebrate and nonvertebrate species, the origin and relationship of these proteins remain unresolved. To address this issue, we employed large-scale genome comparisons to identify genome fragments with conserved synteny and matched these fragments to linkage groups in reconstructed early gnathostome ancestral chromosomes (GAC). This genome comparison revealed that most receptor and peptide genes were clustered in three GAC linkage groups and suggested that the ancestral forms of five peptide subfamilies (corticotropin-releasing hormone-like, calcitonin-like, parathyroid hormone-like, glucagon-like, and growth hormone-releasing hormone-like) and their cognate receptor families emerged through tandem local gene duplications before two rounds (2R) of whole-genome duplication. These subfamily genes have, then, been amplified by 2R whole-genome duplication, followed by additional local duplications and gene loss prior to the divergence of land vertebrates and teleosts. This study delineates a possible evolutionary scenario for whole secretin-like peptide and receptor family members and may shed light on evolutionary mechanisms for expansion of a gene family with a large number of paralogs.

Neurodevelopment and mature brain function are spatiotemporally regulated by various cytokines and chemokines. The chemokine-like neuropeptide FAM19A1 is a member of family with sequence similarity 19 (FAM19), which is predominantly expressed in the brain. Its highly conserved amino acid sequence among vertebrates suggests that FAM19A1 may play important physiological roles in neurodevelopment and brain function. Here we used a LacZ reporter gene system to map the expression pattern of the FAM19A1 gene in the mouse brain. The FAM19A1 expression was observed in several brain regions starting during embryonic brain development. As the brain matured, the FAM19A1 expression was detected in the pyramidal cells of cortical layers 2/3 and 5 and in several limbic areas, including the hippocampus and the amygdala. FAM19A1-deficient mice were used to evaluate the physiological contribution of FAM19A1 to various brain functions. In behavior analysis, FAM19A1deficient mice exhibited several abnormal behaviors, including hyperactive locomotor behavior, longterm memory deficits and fear acquisition failure. These findings provide insight into the potential contributions of FAM19A1 to neurodevelopment and mature brain function. Developmental and physiological processes in the central nervous system (CNS) are tightly regulated by a series of orchestrated gene expressions to promote the formation of dynamic neural circuitries and to execute diverse brain functions 1,2. These gene expressions are heavily influenced by numerous extrinsic factors, including secretory signaling molecules, extracellular matrix proteins, and membrane-bound signaling proteins. In particular, several types of secretory proteins are produced by brain cells and play crucial roles in biological processes in the CNS, including neurogenesis and synaptic plasticity 3-5. Cytokines and chemokines are secretory proteins that mediate a diverse range of functions in the CNS 6. In neural induction process, cytokines are known to act as regulators in the self-renewal of neural stem cells (NSCs) and progenitor differentiation 7,8. Moreover, chemokines, a subclass of cytokines, are involved in neural development. For instance, C-X-C motif chemokine 12 (CXCL12) regulates neural migration and axon pathfinding via the C-X-C chemokine receptor type 4 (CXCR4) signaling pathway 9,10. Furthermore, in the adult nervous system, cytokines such as leukemia inhibitory factor (LIF) control neurotransmitter and neuropeptide profiles 11,12 , whereas interleukin-1 beta (IL-1β) modulates the activity of local neural networks via reconstructing synaptic plasticity and intercellular communication 13,14. Taken together, these findings indicate that the normal development and physiological functions within the CNS depend on the spatiotemporal regulation of several cytokines and chemokines. Given emerging evidence that abnormal cytokine profiles are associated with neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit hyperactive disorder (ADHD), it is im...

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.

Glucose-dependent activation of the homeodomain transcription factor PDX-1 leads to its phosphorylation, to an increase in DNA binding capacity, and to NLS dependent translocation into the nucleus. To uncover unknown mediators of PDX-1 activation, PDX-1 interacting proteins were analysed by pull-down from (32)P-labelled, glucose-stimulated MIN6 cells. Recovered proteins were analysed by 2D gel electrophoresis and mass spectrometry. We identified 14-3-3ε as a novel PDX-1 binding protein and confirmed the interaction in vivo by Fluorescence Resonance Energy Transfer (FRET) analysis. We propose that 14-3-3ε interacts directly with PDX-1 to regulate its cellular distribution in pancreatic beta cells.