Histological analysis of long bones of TrkB mutants.

<p>A, B, and C are stained histological sections from a 4 week old male <i>TrkB^loxp/loxp</i> control; D, E and F are from a male <i>TrkB^loxp/loxp;Col2a1-cre</i> littermate. A, D, H&E staining; B, E, ColX immunostaining; C, F, TrkB immunostaining.</p

Growth defects in <i>MAPK14 ^loxp/loxp;Col2a1-cre</i> mice.

<p>Mean nose-to-tail lengths and body weights±SD for male (A,B) and female (C,D) mice from 1 to 12 weeks after birth, <i>MAPK14 ^loxp/loxp</i> (•), <i>MAPK14 ^loxp/loxp;Col2a1-cre</i> (○), n = 19 for mutants, 20 for controls.</p

Effect of TrkB inhibition on Runx2 and Sox9 expression in ATDC5 cells.

<p>The murine chondrocytic osteosarcoma cells were cultured in differentiation media containing 10 µg/ml insulin and 25 µg/ml ascorbic acid; media was changed every other day for 6 days, at which time the indicated kinase inhibitors were added for an additional 3 days. Real-time RT-PCR was used to quantify mRNA levels of the marker proteins. Data points were calculated using the ΔΔCt method and represent the mean ±SD of real-time data from five sample pairs, expressed as fold difference from insulin alone (the calibrator). *, <i>P</i><0.001.</p

Proposed model of BDNF/TrkB regulation of chondrocyte differentiation via p38 activation.

<p>Unopposed IGF-I action favors suppression of Runx2 and Sox9 expression and proliferation, whereas BDNF binding to TrkB results in increased p38 activity, decreased ERK activity, increased Runx2 and Sox9 expression, and ultimately hypertrophic differentiation.</p

Histological analysis of TrkB mutants for phospho-p38.

<p>A, B, are stained histological sections from a 4 week old male <i>TrkB^loxp/loxp</i> control; C, D are from a male <i>TrkB^loxp/loxp;Col2a1-cre</i> littermate. A, C, H&E staining; B, D, phospho-p38 staining.</p

Growth defects in <i>TrkB ^loxp/loxp;Col2a1-cre</i> mice.

<p>A, Gross appearance of TrkB mutant female and control female littermate at 10 days of age. B–D, mean nose-to-tail lengths and body weights ±SD for male (B,C) and female (D,E) mice from 1 to 12 weeks after birth; <i>TrkB ^loxp/loxp</i> (•), <i>TrkB ^loxp/loxp;Col2a1-cre</i> (○), n = 23 for mutants, 22 for controls.</p

Isoxazole Alters Metabolites and Gene Expression, Decreasing Proliferation and Promoting a Neuroendocrine Phenotype in β‑Cells

Novel strategies are needed to modulate β-cell differentiation and function as potential β-cell replacement or restorative therapies for diabetes. We previously demonstrated that small molecules based on the isoxazole scaffold drive neuroendocrine phenotypes. The nature of the effects of isoxazole compounds on β-cells was incompletely defined. We find that isoxazole induces genes that support neuroendocrine and β-cell phenotypes and suppresses genes important for proliferation. Isoxazole alters β-cell metabolites and protects glucose-responsive signaling pathways under lipotoxic conditions. Finally, we show that isoxazole improves glycemia in a mouse model of β-cell regeneration. Isoxazole is a prime candidate to alter cell fate in different contexts

Isoxazole Alters Metabolites and Gene Expression, Decreasing Proliferation and Promoting a Neuroendocrine Phenotype in β‑Cells

Novel strategies are needed to modulate β-cell differentiation and function as potential β-cell replacement or restorative therapies for diabetes. We previously demonstrated that small molecules based on the isoxazole scaffold drive neuroendocrine phenotypes. The nature of the effects of isoxazole compounds on β-cells was incompletely defined. We find that isoxazole induces genes that support neuroendocrine and β-cell phenotypes and suppresses genes important for proliferation. Isoxazole alters β-cell metabolites and protects glucose-responsive signaling pathways under lipotoxic conditions. Finally, we show that isoxazole improves glycemia in a mouse model of β-cell regeneration. Isoxazole is a prime candidate to alter cell fate in different contexts

Isoxazole Alters Metabolites and Gene Expression, Decreasing Proliferation and Promoting a Neuroendocrine Phenotype in β‑Cells

Novel strategies are needed to modulate β-cell differentiation and function as potential β-cell replacement or restorative therapies for diabetes. We previously demonstrated that small molecules based on the isoxazole scaffold drive neuroendocrine phenotypes. The nature of the effects of isoxazole compounds on β-cells was incompletely defined. We find that isoxazole induces genes that support neuroendocrine and β-cell phenotypes and suppresses genes important for proliferation. Isoxazole alters β-cell metabolites and protects glucose-responsive signaling pathways under lipotoxic conditions. Finally, we show that isoxazole improves glycemia in a mouse model of β-cell regeneration. Isoxazole is a prime candidate to alter cell fate in different contexts

Isoxazole Alters Metabolites and Gene Expression, Decreasing Proliferation and Promoting a Neuroendocrine Phenotype in β‑Cells

Novel strategies are needed to modulate β-cell differentiation and function as potential β-cell replacement or restorative therapies for diabetes. We previously demonstrated that small molecules based on the isoxazole scaffold drive neuroendocrine phenotypes. The nature of the effects of isoxazole compounds on β-cells was incompletely defined. We find that isoxazole induces genes that support neuroendocrine and β-cell phenotypes and suppresses genes important for proliferation. Isoxazole alters β-cell metabolites and protects glucose-responsive signaling pathways under lipotoxic conditions. Finally, we show that isoxazole improves glycemia in a mouse model of β-cell regeneration. Isoxazole is a prime candidate to alter cell fate in different contexts