Identification and characterization of an endogenous chemotactic ligand specific for FPRL2

Chemotaxis of dendritic cells (DCs) and monocytes is a key step in the initiation of an adequate immune response. Formyl peptide receptor (FPR) and FPR-like receptor (FPRL)1, two G protein-coupled receptors belonging to the FPR family, play an essential role in host defense mechanisms against bacterial infection and in the regulation of inflammatory reactions. FPRL2, the third member of this structural family of chemoattractant receptors, is characterized by its specific expression on monocytes and DCs. Here, we present the isolation from a spleen extract and the functional characterization of F2L, a novel chemoattractant peptide acting specifically through FPRL2. F2L is an acetylated amino-terminal peptide derived from the cleavage of the human heme-binding protein, an intracellular tetrapyrolle-binding protein. The peptide binds and activates FPRL2 in the low nanomolar range, which triggers intracellular calcium release, inhibition of cAMP accumulation, and phosphorylation of extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases through the G(i) class of heterotrimeric G proteins. When tested on monocytes and monocyte-derived DCs, F2L promotes calcium mobilization and chemotaxis. Therefore, F2L appears as a new natural chemoattractant peptide for DCs and monocytes, and the first potent and specific agonist of FPRL2.     

MERTK mutation update in inherited retinal diseases

MER tyrosine kinase (MERTK) encodes a surface receptor localized at the apical membrane of the retinal pigment epithelium. It plays a critical role in photoreceptor outer segment internalization prior to phagocytosis. Mutations in MERTK have been associated with severe autosomal recessive retinal dystrophies in the RCS rat and in humans. We present here a comprehensive review of all reported MERTK disease causing variants with the associated phenotype. In addition, we provide further data and insights of a large cohort of 1,195 inherited retinal dystrophies (IRD) index cases applying state‐of‐the‐art genotyping techniques and summarize current knowledge. A total of 79 variants have now been identified underlying rod‐cone dystrophy and cone‐rod dystrophy including 11 novel variants reported here. The mutation spectrum in MERTK includes 33 missense, 12 nonsense, 12 splice defects, 12 small deletions, 2 small insertion–deletions, 3 small duplications, and 2 exonic and 3 gross deletions. Altogether, mutations in MERTK account for ～2% of IRD cases with a severe retinal phenotype. These data are important for current and future therapeutic trials including gene replacement therapy or cell‐based therapy.     

Cerebellar asymmetry,cortical asymmetry and handedness: Two independent networks

ABSTRACT

In 46 right-handers and 46 left-handers, we used functional magnetic resonance imaging to record activity in the frontal lobes while they generated words, the temporal lobe while they made synonym judgments, and the parietal lobe while they watched videos of manual actions. In each case we also recorded activity in the cerebellum. Laterality indices showed a significant left-hemispheric bias in each cortical lobe and a right-hemispheric bias in the cerebellum for the 2 language tasks, but not during action observation. Cerebellar asymmetry also correlated negatively with frontal and temporal asymmetry, reflecting contralateral connections, but not with parietal asymmetry. A factor analysis of the inter-correlations among laterality indices revealed 2 factors, implying independent lateralized networks, with cerebellar asymmetry strongly linked to a language network in frontal and temporal cortices, and handedness strongly linked to an action-observation network in the parietal lobe.