Abstract
The role of cells of the diffuse neuroendocrine system in development and maintenance of individual organs and tissues remains poorly understood. Here we identify a regulatory region sufficient for accurate in vivo expression of synaptophysin (SYP), a common marker of neuroendocrine differentiation, and report generation of Tg(Syp-EGFPloxP-DTA)147Ayn (SypELDTA) mice suitable for flexible organ-specific ablation of neuroendocrine cells. These mice express EGFP and diphtheria toxin fragment A (DTA) in SYP positive cells before and after Cre-loxP mediated recombination, respectively. As a proof of principle, we have crossed SypELDTA mice with EIIA-Cre and PB-Cre4 mice. EIIA-Cre mice express Cre recombinase in a broad range of tissues, while PB-Cre4 mice specifically express Cre recombinase in the prostate epithelium. Double transgenic EIIA-Cre; SypELDTA embryos exhibited massive cell death in SYP positive cells. At the same time, PB-Cre4; SypELDTA mice showed a substantial decrease in the number of neuroendocrine cells and associated prostate hypotrophy. As no increase in cell death and/or Cre-loxP mediated recombination was observed in non-neuroendocrine epithelium cells, these results suggest that neuroendocrine cells play an important role in prostate development. High cell type specificity of Syp locus-based cassette and versatility of generated mouse model should assure applicability of these resources to studies of neuroendocrine cell functions in various tissues and organs.
Highlights
Neuroendocrine (NE) cells have both neuronal and endocrine phenotypes [1]
The diffuse neuroendocrine system (DNES) is composed of NE cells scattered throughout the entire body either as single cells or clusters, such as solitary pulmonary NE cells (PNECs) and neuroepithelial bodies (NEBs) [2], the islets of Langerhans in the pancreas [3,4], gastrointestinal NE cells [5,6], dermal NE cells [7], adrenal medullary NE cell [8,9,10], and prostate NE cells [11]
It may imply that neuron-restrictive silencer element (NRSE) and the sequences of those conserved regions are involved in conferring the cell type specific expression of SYP
Summary
Neuroendocrine (NE) cells have both neuronal and endocrine phenotypes [1]. The diffuse neuroendocrine system (DNES) is composed of NE cells scattered throughout the entire body either as single cells or clusters, such as solitary pulmonary NE cells (PNECs) and neuroepithelial bodies (NEBs) [2], the islets of Langerhans in the pancreas [3,4], gastrointestinal NE cells [5,6], dermal NE cells (so-called Merkel cells) [7], adrenal medullary NE cell [8,9,10], and prostate NE cells [11]. PNECs are implicated in regulation of lung maturation and growth, function as oxygensensing chemoreceptors and are likely important for lung stem cell niches [2]. Though there has been progress in understanding the function of NE cells, the physiological role of NE cells in most other organs is not well understood. Cells with NE differentiation are present in many cancer types, with their representation ranging from being the major component in small cell carcinomas of the lung [2] and prostate [12], as well as NE tumors of gastrointestinal tract [13], to more limited quantity in other cancers, such as adenocarcinomas of the lung [2] and prostate [12]. The cell of origin of neoplastic NE cells and their contribution to cancer progression remain insufficiently elucidated [1,2,12,14]
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