ABSTRACT
Recent evidence suggests that alterations in the self-renewal program of stem/progenitor cells can cause tumorigenesis. By utilizing genetically engineered mouse models of neurofibromatosis type 1 (NF1), we demonstrated that plexiform neurofibroma, the only benign peripheral nerve sheath tumor with potential for malignant transformation, results from Nf1 deficiency in fetal stem/progenitor cells of peripheral nerves. Surprisingly, this did not cause hyperproliferation or tumorigenesis in early postnatal period. Instead, peripheral nerve development appeared largely normal in the absence of Nf1 except for abnormal Remak bundles, the nonmyelinated axon-Schwann cell unit, identified in postnatal mutant nerves. Subsequent degeneration of abnormal Remak bundles was accompanied by initial expansion of nonmyelinating Schwann cells. We suggest abnormally differentiated Remak bundles as a cell of origin for plexiform neurofibroma.
Subject(s)
Myelin Sheath/pathology , Neurofibroma/pathology , Schwann Cells/pathology , Animals , Biomarkers/metabolism , Cell Lineage , Cell Proliferation , Disease Progression , Fetus/cytology , Fetus/metabolism , Gene Targeting , Glial Fibrillary Acidic Protein/metabolism , Integrases/metabolism , Mice , Mutation/genetics , Neurofibromin 1/metabolism , Receptor, Nerve Growth Factor/metabolism , Recombination, Genetic , Sciatic Nerve/embryology , Sciatic Nerve/pathology , Sciatic Nerve/ultrastructure , Stem Cells/cytology , Stem Cells/metabolismABSTRACT
OBJECTIVE: To determine the tear production in dogs admitted to an intensive care unit (ICU). DESIGN: Prospective observational study from November 2010-September 2011. SETTING: Private emergency and referral hospital. ANIMALS: Thirty healthy control dogs and 30 dogs hospitalized in an ICU for treatment of systemic illness without previously diagnosed ophthalmic disorders and no recent history of anesthesia. Enrollment was based on availability of the ophthalmologist within 24 hours of admission to the ICU. INTERVENTIONS: Tear production was measured utilizing Schirmer tear test strips (STT) in healthy control animals as well as in hospitalized canine patients. All patients received an ophthalmic examination by a board-certified veterinary ophthalmologist within 24 hours of admission to the ICU. Lubrication with artificial tear gel every 2-4 hours as needed was implemented after STT was measured. MEASUREMENTS AND MAIN RESULTS: Average tear productions in the control and canine ICU populations were 24.5 mm/min and 13.2 mm/min, respectively. This was found to be statistically significant (P < 0.001). Furthermore, there was a trend toward a decrease in tear production in patients with kidney disease and a trend toward normal tear production in patients with cardiac disease but the sample size was likely too small to enable detection of a statistically significant difference. CONCLUSIONS: This study demonstrates a decrease in tear production in canine ICU patients. While further study is warranted to determine how different diseases impact tear production, these finding support the implementation of frequent ocular lubrication in all ICU patients.
Subject(s)
Tears/physiology , Animals , Dogs , Female , Hospitals, Animal , Intensive Care Units , Male , Reagent StripsABSTRACT
Loss of neurofibromin, the protein product of the tumor suppressor gene neurofibromatosis type 1 (NF1), is associated with neurofibromas, composed largely of Schwann cells. The number and size of neurofibromas in NF1 patients have been shown to increase during pregnancy. A mouse embryonic stem cell (mESC) model was used, in which mESCs with varying levels of neurofibromin were differentiated into Schwann-like cells. NF1 cell lines derived from a malignant and a benign human tumor were used to study proliferation in response to hormones. Estrogen and androgen receptors were not expressed or expressed at very low levels in the NF1+/+ cells, at low levels in NF1+/-cells, and robust levels in NF1-/-cells. A 17beta-estradiol (E2) metabolite, 2-methoxy estradiol (2ME2) is cytotoxic to the NF1-/- malignant tumor cell line, and inhibits proliferation in the other cell lines. 2ME2 or its derivatives could provide new treatment avenues for NF1 hormone-sensitive tumors at times of greatest hormonal influence.
Subject(s)
Embryonic Stem Cells/physiology , Estradiol/analogs & derivatives , Neurofibroma/physiopathology , Neurofibromin 1/metabolism , Schwann Cells/drug effects , Schwann Cells/physiology , 2-Methoxyestradiol , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , DNA Primers/genetics , Embryonic Stem Cells/cytology , Estradiol/toxicity , Humans , Immunohistochemistry , In Situ Nick-End Labeling , Mice , Neurofibroma/metabolism , Neurofibromin 1/genetics , Receptors, Estradiol/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Schwann Cells/cytologyABSTRACT
The expression of midbrain homeobox-1 (mbx1) defines a discrete region in the vertebrate neural plate that will give rise to the mesencephalon, as well as subregions of the diencephalon and retinal field. Here, we report on the identification and cloning of a second Mbx gene in zebrafish, termed mbx2. Genomic sequence comparison suggests that mbx1 and mbx2 are derived from the duplication of a single putative ancestral gene that is conserved in other vertebrates as a single copy gene. Furthermore, phylogenetic analyses indicate that the mbx genes belong to a novel subgroup of paired-like homeobox genes. Finally, quantitative reverse transcriptase-PCR and whole mount in situ hybridization experiments revealed a pattern of partial spatiotemporal expression divergence between the mbx paralogs that correlates with sequence divergence in noncoding regulatory domains. Our data support a subfunctionalization model that may explain the retention of duplicate mbx genes in teleosts.