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Abstract:
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The purpose of the thesis is to explore the role of BMP signaling in developing vertebrate midbrain . BMP signaling plays important roles in various tissues and stages of neural development to regulate cell fate , proliferation , differentiation , morphogenesis and more . We observed that several major BMPs are expressed not only at the roof plate but also the floor plate of the midbrain . This has led us to ask the role of BMP signaling in dorsal and ventral midbrain patterning . Despite ventral experiments , we found that BMP signaling does not regulate ventral cell fate specification in the midbrain . Instead BMPs profoundly influence the shape and early morphogenesis of the midbrain neural plate as it closes into a neural tube .
During neural tube closure , one of the early events occurring at the ventral midline is median hinge point (MHP ) formation . Failure to form MHP leads to neural tube closure defects , the 2nd most common birth defects in humans . However , the molecular mechanisms underlying MHP formation are not well known . We found that the lowest BMP signaling occurs at the MHP during early neurulation and BMP blockade is necessary and sufficient for MHP formation . Interestingly , we also demonstrated that BMP blockade directs MHP formation by regulating the apicobasal polarity pathway and this regulation may be mediated by biochemical interactions between pSMAD5 and the apical protein , PAR3 . Additionally , our time -lapse data suggest that BMP blockade slows cell cycle progression by increasing duration of G1 to S transition and S phase which leads cell nuclei stay at the basal location longer . This mimics basal nuclear migration seen at the MHP where low BMP signaling occurs . Thus , we conclude that BMP signaling regulates neural tube closure via the apicobasal polarity pathway and in a cell cycle dependent manner at the ventral midline .
We observed that BMP signaling is necessary and sufficient for the dorsal cell fate specification in a context -dependent manner and ventral BMP signaling affects dorsal cell fates .
Taken together , we propose the idea that BMP signaling has distinct roles in different contexts . BMPs regulate tissue morphogenesis in the ventral midbrain and dorsally cell fate specification . |