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The Journal of Neuroscience, February 15, 2006, 26(7):1896-1905; doi:10.1523/JNEUROSCI.3202-05.2006

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Development/Plasticity/Repair
Genetic Analyses Demonstrate That Bone Morphogenetic Protein Signaling Is Required for Embryonic Cerebellar Development

Lihua Qin,^1,4 Lara Wine-Lee,^1,3 Kyung J. Ahn,¹ and E. Bryan Crenshaw, III^1,2,3

¹Mammalian Neurogenetics Group, Center for Childhood Communication, Division of Pediatric Otolaryngology, The Children’s Hospital of Philadelphia, and ²Department of Otorhinolaryngology: Head and Neck Surgery and ³Neuroscience Graduate Group, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, and ⁴Department of Anatomy, Peking University Health Science Center, Beijing, China 100083

Correspondence should be addressed to Dr. E. Bryan Crenshaw III, Mammalian Neurogenetics Group, Center for Childhood Communication, The Children’s Hospital of Philadelphia, 34th and Civic Center Boulevard, Philadelphia, PA 19104. Email: crenshaw{at}email.chop.edu

The cerebellum has been a useful model for studying many aspects of neural development because of its relatively simple cytoarchitecture and developmental program. Yet, the genetic mechanisms underlying early differentiation and patterning of the cerebellum are still poorly characterized. Cell expression studies and culture experiments have suggested the importance of bone morphogenetic proteins (BMPs) in development of specific populations of cerebellar neurons. Here, we examined mice with targeted mutations in the BMP type I receptor genes Bmpr1a and Bmpr1b, to genetically test the hypothesis that BMPs play an inductive role in the embryogenesis of cerebellar granule cells. In Bmpr1a;Bmpr1b double knock-out mice, severe cerebellar patterning defects are observed resulting in smaller cerebella that are devoid of foliation. In mutants containing either single BMP receptor gene mutation alone, cerebellar histogenesis appears normal, thereby demonstrating functional redundancy of type I BMP receptors during cerebellar development. Loss of BMP signaling in double mutant animals leads to a dramatic reduction in the number of cerebellar granule cells and ectopic location of many of those that remain. Molecular markers of granule cell specification, including Math1 and Zic1, are drastically downregulated. In addition, Purkinje cells are disorganized and ectopically located, but they appear to be correctly specified. Consistent with the interpretation that granule cells alone are affected, phosphorylated Smad1/5/8 is immunolocalized predominantly to granule cell precursors and not appreciably detected in Purkinje cell precursors. This study demonstrates that BMP signaling plays a crucial role in the specification of granule cells during cerebellar development.

Key words: bone morphogenetic protein receptor type I; Cre-mediated conditional Bmpr1a knock-out; Bmpr1b mutant; cerebellar development; external granular layer; granule cells; Purkinje cells

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Received Aug. 1, 2005; revised Dec. 17, 2005; accepted Dec. 21, 2005.

Correspondence should be addressed to Dr. E. Bryan Crenshaw III, Mammalian Neurogenetics Group, Center for Childhood Communication, The Children’s Hospital of Philadelphia, 34th and Civic Center Boulevard, Philadelphia, PA 19104. Email: crenshaw{at}email.chop.edu

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