Biomedical subjects

John A Kessler

Publications and source records attributed to John A Kessler.

21 records · Page 2Linked to original sources

PubMed2003

Transgenic overexpression of BMP4 increases astroglial and decreases oligodendroglial lineage commitment.

Bone morphogenetic proteins (BMPs) promote astrocytic differentiation of cultured subventricular zone stem cells. To determine whether BMPs regulate the astrocytic lineage in vivo, transgenic mice were constructed that overexpress BMP4 under control of the neuron-specific enolase (NSE) promoter. Overexpression of BMP4 was first detectable by Western analysis on embryonic day 16 and persisted into the adult. The overexpression of BMP4 resulted in a remarkable 40% increase in the density of astrocytes in multiple brain regions accompanied by a decrease in the density of oligodendrocytes ranging between 11 and 26%, depending on the brain region and the developmental stage. No changes in neuron numbers or the pattern of myelination were detected, and there were no gross structural abnormalities. Similar phenotypes were observed in three independently derived transgenic lines. Coculture of transgenic neurons with neural progenitor cells significantly enhanced astrocytic lineage commitment by the progenitors; this effect was blocked by the BMP inhibitor Noggin, indicating that the stimulation of astrogliogenesis was due to BMP4 release by the transgenic neurons. These observations suggest that BMP4 directs progenitor cells in vivo to commit to the astrocytic rather than the oligodendroglial lineage. Further, differentiation of radial glial cells into astrocytes was accelerated, suggesting that radial glia were a source of at least some of the supernumerary astrocytes. Therefore, BMPs are likely important mediators of astrocyte development in vivo.

Animals↗

PubMed2002

Msx2 and p21(CIP1/WAF1) mediate the proapoptotic effects of bone morphogenetic protein-4 on ventricular zone progenitor cells.

Treatment of cultured ventricular zone (VZ) progenitor cells with bone morphogenetic protein-4 (BMP4) promoted cell death in a dose-dependent manner. VZ progenitor cells became progressively more resistant to the proapoptotic effects of BMP4 between E10 and E16, and, by E18 and thereafter, BMP4 treatment no longer led to progenitor cell death. BMP4 treatment of E13 progenitor cells promoted expression of msx2 and p21(CIP1/WAF1) (p21) and inhibition of expression of either gene prevented BMP4-mediated apoptosis. Treatment of E18 cells with BMP4 failed to induce apoptosis but still induced expression of low levels of msx2 and p21. Knockout of bax significantly reduced but did not prevent BMP4-mediated death of E13 murine progenitor cells. These observations indicate that msx2 and p21 mediate the proapoptotic effects of BMP4 on VZ progenitor cells and that each gene is necessary but insufficient to promote apoptosis.

Animals↗

PubMed2002

In vivo evidence that BMP signaling is necessary for apoptosis in the mouse limb.

To determine the role of Bone morphogenetic protein (BMP) signaling in murine limb development in vivo, the keratin 14 promoter was used to drive expression of the BMP antagonist Noggin in transgenic mice. Phosphorylation and nuclear translocation of Smad1/5 were dramatically reduced in limbs of the transgenic animals, confirming the inhibition of BMP signaling. These mice developed extensive limb soft tissue syndactyly and postaxial polydactyly. Apoptosis in the developing limb necrotic zones was reduced with incomplete regression of the interdigital tissue. The postaxial extra digit is also consistent with a role for BMPs in regulating apoptosis. Furthermore, there was persistent expression of Fgf8, suggesting a delay in the regression of the AER. However, Msx1 and Msx2 expression was unchanged in these transgenic mice, implying that induction of these genes is not essential for mediating BMP-induced interdigital apoptosis in mice. These abnormalities were rescued by coexpressing BMP4 under the same promoter in double transgenic mice, suggesting that the limb abnormalities are a direct effect of inhibiting BMP signaling.

Animals↗