Bone Morphogenetic Protein 7 Regulates Sensory Neurogenesis

• Author / Creator

  Sabiri, Peter

• Background: The trigeminal ganglion (TG) is a cluster of neuron bodies in the cranium that supplies the face and skull with sensory innervation. In the mouse, neurons of the TG supply the whisker pad that is important for spatial navigation and intraspecific communication. Specialized cells in the TG can detect tactile stimuli, positional stimuli, and pain. The origin of these neurons is thought to be the neural crest and the neuroectoderm. Previous studies have established that early neurogenesis requires the activation of neurogenin 1 and 2 (Ngn1/2), early growth response protein 2 (Egr2) and brain-specific homeobox protein 3a (Brn3a) to specify neural crest cells to sensory neurons. Subsequently, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophins 3 and 4 (NT3/NT4), produced by target tissues, are required for nerve subtype specification, target innervation, and survival. Recently, bone morphogenetic proteins (Bmps) have been implicated to participate in these processes by retrograde signaling. Bmps are secreted peptides that are important for cell survival, differentiation, and homeostasis. Currently, it is not known which or how Bmps regulate sensory nerve development. Here we demonstrate an altered sensory phenotype in mice carrying a complete and neural crest-specific (Wnt1-cre) deletion of Bmp7. Methods: Embryos were harvested from mice carrying either a complete deletion (Bmp7∆/∆) or a conditional deletion of Bmp7 in the neural crest (Bmp7fl/fl Wnt1-cre) and characterized using histological, immunohistochemical, and gene expression analysis (qPCR) of various sensory neuronal receptors, peptides, and transcription factors (TrkA, TrpV1, CGRP, Runx1, Ret for nociceptive neurons; TrkB, TrkC, Runx3, Ret for mechano-and proprioceptive neurons). The whisker pads of adult mice carrying a neural crest-specific deletion of Bmp7 were tested with a 15 psi air puff current to determine whether molecular differences result in physiological changes. Results: The trigeminal ganglion in embryos carrying a full and conditional deletion of Bmp7 is morphologically altered, appearing to be smaller and slightly misshapen in comparison to wild-type littermates. In addition, qPCR analysis shows mRNA differences in some receptors, pain associated peptides, and transcription factors (TrkA, Trpv1, Ret, CGRP, Runx1), indicative of an increased nociceptor phenotype or a delay in neuronal development. At 15psi air pressures, conditional knockout mice were less mechanosensitive and more pain sensitive. Conclusion: Bmp7 is important for peripheral nerve development. Gene expression analysis reveals that sensory neurons of mutants may have an increased nociceptor phenotype or may be delayed in development. Immunohistochemical analyses established that the TGs are smaller and misshapen in mutants. Air puff assays indicate that Wnt1-cre mutants have an inhibited mechano-response, but a hyperalgesic response. Future experiments will elucidate the mechanisms by which these changes occur.

• Subjects / Keywords

  • Trigeminal ganglion
  • Sensory Neurogenesis
  • Mouse genetics
  • Development
  • Bmp

• Graduation date

  Fall 2017

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/R3CV4C760

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.