Neuregulin-1 (NRG-1) signaling has been implicated in inductive interactions between pre- and postsynaptic partners during synaptogenesis. We used gene targeting to selectively disrupt cysteine-rich domain-(CRD-) containing NRG-1 isoforms. In CRD-NRG-1-/-mice, peripheral projections defasciculated and displayed aberrant branching patterns within their targets. Motor nerve terminals were transiently associated with broad bands of postsynaptic ACh receptor (AChR) clusters. Initially, Schwann cell precursors accompanied peripheral projections, but later, Schwann cells were absent from axons in the periphery. Following initial stages of synapse formation, sensory and motor nerves withdrew and degenerated. Our data demonstrate the essential role of CRD-NRG-1-mediated signaling for coordinating nerve, target, and Schwann cell interactions in the normal maintenance of peripheral synapses, and ultimately in the survival of CRD-NRG-1-expressing neurons.

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Transmembrane isoforms of neuregulin-1 (Nrg-1), ligands for erbB receptors, include an extracellular domain with an EGF-like sequence and a highly conserved intracellular domain (ICD) of unknown function. In this paper, we demonstrate that transmembrane isoforms of Nrg-1 are bidirectional signaling molecules in neurons. The stimuli for Nrg-1 back signaling include binding of erbB receptor dimers to the extracellular domain of Nrg-1 and neuronal depolarization. These stimuli elicit proteolytic release and translocation of the ICD of Nrg-1 to the nucleus. Once in the nucleus, the Nrg-1 ICD represses expression of several regulators of apoptosis, resulting in decreased neuronal cell death in vitro. Thus, regulated proteolytic processing of Nrg-1 results in retrograde signaling that appears to mediate contact and activity-dependent survival of Nrg-1–expressing neurons.

Pseudomelanocytic nests in the setting of lichenoid inflammation can mimic atypical melanocytic proliferations. Both melanocytic and cytokeratin immunohistochemical stains may be utilized to differentiate these entities. Unlike true melanocytic nests, pseudomelanocytic nests contain Melanoma Antigen Recognized by T-cells 1 (MART-1)/ Melan-A-positive cells and cells positive for pan-cytokeratins, CD3 and/or CD68. Recently, rare (1-2 cells/nest) microphthalmia- associated transcription factor (MiTF)-positive cells were also reported in pseudomelanocytic nests. We present a 48-year-old man with a 2 × 3 cm violaceous to hyperpigmented, non-blanching, polygonal patch on the neck. Histopathology showed focal epidermal atrophy, irregularly distributed junctional nests and a lichenoid infiltrate with colloid bodies. Immunoperoxidase studies revealed occasional pan-cytokeratin and MART-1/Melan-A-positive staining in nests as well as focal S-100 protein-positive cells. Importantly, the majority of nests showed numerous cells positive for MiTF and SOX10 (>2 cells/nest and some the majority of cells). This combined staining pattern confounds the above-described immunohistochemical distinction between pseudo and true melanocytic nests. Clinically felt to represent unilateral lichen planus pigmentosus/erythema dyschromicum perstans and not malignant melanoma in situ, this lesion highlights the importance of clinicopathologic correlation and suggests either a new melanocytic entity or a novel pattern of benign melanocytic reorganization in a subset of lichenoid dermatitides.

Mycosis fungoides (MF) is characterized by skin accumulation of CCR4+CCR7- effector memory T cells; however the mechanism for their recruitment is not clearly identified. Thymic Stromal Lymphopoietin (TSLP) is a keratinocyte-derived cytokine that triggers Th2 immunity and is associated with T cell recruitment to the skin in atopic dermatitis. Interleukin-16 (IL-16) is a chemoattractant and growth factor for CD4+T cells. We hypothesized that TSLP and IL-16 could contribute to recruitment of malignant T cells in MF. We found elevated TSLP and IL-16 in very early stage patients' plasma and skin biopsies, prior to elevation in CCL22. Both TSLP and IL-16 induced migratory responses of CCR4+TSLPR+CD4+CCR7-CD31+cells, characteristic of malignant T cells in the skin. Co-stimulation also resulted in significant proliferative responses. We conclude that TSLP and IL-16, expressed at early stages of disease, function to recruit malignant T cells to the skin and contribute to their enhanced proliferation.