Inhibition of spleen tyrosine kinase attenuates IgE-mediated airway contraction and mediator release in human precision cut lung slices.

Background And Purpose: Asthma presents as a heterogeneous syndrome characterized by airway obstruction, inflammation and hyper-reactivity (AHR). Spleen tyrosine kinase (Syk) mediates allergen-induced mast cell degranulation, a central component of allergen-induced inflammation and AHR. However, the role of Syk in IgE-mediated constriction of human small airways remains unknown.

Inhibition of spleen tyrosine kinase attenuates allergen-mediated airway constriction.

Spleen tyrosine kinase (SYK) is a key activator of signaling pathways downstream of multiple surface receptors implicated in asthma. SYK function has been extensively studied in mast cells downstream of the high-affinity IgE receptor, FcεR1. Preclinical studies have demonstrated a role for SYK in models of allergic inflammation, but a role in airway constriction has not been demonstrated.

Cell expression of GDAP1 in the nervous system and pathogenesis of Charcot-Marie-Tooth type 4A disease.

Mutations in the mitochondrial protein GDAP1 are the cause of Charcot-Marie-Tooth type 4A disease (CMT4A), a severe form of peripheral neuropathy associated with either demyelinating, axonal or intermediate phenotypes. GDAP1 is located in the outer mitochondrial membrane and it seems that may be related with the mitochondrial network dynamics. We are interested to define cell expression in the nervous system and the effect of mutations in mitochondrial morphology and pathogenesis of the disease.

Genetic and physiological evidence that oligodendrocyte gap junctions contribute to spatial buffering of potassium released during neuronal activity.

Mice lacking the K+ channel Kir4.1 or both connexin32 (Cx32) and Cx47 exhibit myelin-associated vacuoles, raising the possibility that oligodendrocytes, and the connexins they express, contribute to recycling the K+ evolved during neuronal activity. To study this possibility, we first examined the effect of neuronal activity on the appearance of vacuoles in mice lacking both Cx32 and Cx47.

ErbB2 signaling in Schwann cells is mostly dispensable for maintenance of myelinated peripheral nerves and proliferation of adult Schwann cells after injury.

Neuregulin/erbB signaling is critically required for survival and proliferation of Schwann cells as well as for establishing correct myelin thickness of peripheral nerves during development. In this study, we investigated whether erbB2 signaling in Schwann cells is also essential for the maintenance of myelinated peripheral nerves and for Schwann cell proliferation and survival after nerve injury. To this end, we used inducible Cre-loxP technology using a PLP-CreERT2 allele to ablate erbB2 in adult Schwann cells.

Both laminin and Schwann cell dystroglycan are necessary for proper clustering of sodium channels at nodes of Ranvier.

Nodes of Ranvier are specialized axonal domains, at which voltage-gated sodium channels cluster. How axons cluster molecules in discrete domains is mostly unknown. Both axons and glia probably provide constraining mechanisms that contribute to domain formation.

Prenylation-defective human connexin32 mutants are normally localized and function equivalently to wild-type connexin32 in myelinating Schwann cells.

Mutations in GJB1, the gene encoding the gap junction protein connexin32 (Cx32), cause the X-linked form of Charcot-Marie-Tooth disease, an inherited demyelinating neuropathy. The C terminus of human Cx32 contains a putative prenylation motif that is conserved in Cx32 orthologs. Using [3H]mevalonolactone ([3H]MVA) incorporation, we demonstrated that wild-type human connexin32 can be prenylated in COS7 cells, in contrast to disease-associated mutations that are predicted to disrupt the prenylation motif.

Acute demyelination disrupts the molecular organization of peripheral nervous system nodes.

Intraneurally injected lysolecithin causes both segmental and paranodal demyelination. In demyelinated internodes, axonal components of nodes fragment and disappear, glial and axonal paranodal and juxtaparanodal proteins no longer cluster, and axonal Kv1.1/Kv1.

Expression analysis of the N-Myc downstream-regulated gene 1 indicates that myelinating Schwann cells are the primary disease target in hereditary motor and sensory neuropathy-Lom.

Mutations in the gene encoding N-myc downstream-regulated gene-1 (NDRG1) lead to truncations of the encoded protein and are associated with an autosomal recessive demyelinating neuropathy--hereditary motor and sensory neuropathy-Lom. NDRG1 protein is highly expressed in peripheral nerve and is localized in the cytoplasm of myelinating Schwann cells, including the paranodes and Schmidt-Lanterman incisures. In contrast, sensory and motor neurons as well as their axons lack NDRG1.

Connexins are critical for normal myelination in the CNS.

Mutations in Cx32, a gap-junction channel-forming protein, result in X-linked Charcot-Marie-Tooth disease, a demyelinating disease of the peripheral nervous system. However, although oligodendrocytes express Cx32, central myelination is unaffected. To explore this discrepancy, we searched for additional oligodendrocyte connexins.

Identification of genes that are downregulated in the absence of the POU domain transcription factor pou3f1 (Oct-6, Tst-1, SCIP) in sciatic nerve.

Despite the importance of myelinating Schwann cells in health and disease, little is known about the genetic mechanisms underlying their development. The POU domain transcription factor pou3f1 (Tst-1, SCIP, Oct-6) is required for the normal differentiation of myelinating Schwann cells, but its precise role requires identification of the genes that it regulates. Here we report the isolation of six genes whose expression is reduced in the absence of pou3f1.