Stem cells are self-renewing multipotent progenitors with the broadest developmental potential in a given tissue at a given time (Morrison et al. Cell 88:287). There is great interest in neural stem cells because of their importance in neural development and their therapeutic potential. Neural crest stem cells (NCSCs) migrate out of the neural tube in early to mid-gestation, and give rise to the peripheral nervous system (PNS) as well as other tissues. In order to understand PNS formation, the process by which NCSCs differentiate into the diverse cell types of the PNS must be understood. Although neural crest cells were thought to differentiate within days of migrating, we have recently discovered that NCSCs persist into late gestation by self-renewing within peripheral nerves (Morrison et al. Cell 96:737). This observation suggests that PNS development may be more dynamic than previously thought and raises several specific questions. First, why would the self-renewal of NCSCs be promoted within peripheral nerves if, as current models suggest, the neural crest only gives rise to Schwann cells in nerves? Aim #1 is to use CRE-recombinase fate mapping to test whether the neural crest actually gives rise to multiple lineages of cells within nerves. If so, nerve development would require multilineage differentiation by stem cells rather than just overt differentiation by Schwann precursors. This would fundamentally change models of nerve development.
Aim #2 is to test whether postmigratory NCSCs also persist in other areas of the fetal PNS.
Aim #4 is to test whether there are cell-intrinsic differences between these NCSC populations from different regions of the PNS in terms of the types of neurons they can form. If there are cell-intrinsic differences between postmigratory NCSC populations then perhaps differences between stem cell lineages interact with environmental differences to generate neural diversity.
Aim #3 is to test whether rare NCSCs also persist postnatally. The discovery of NCSCs in postnatal tissues might fundamentally alter approaches to regeneration in the PNS. Answers to these questions could change the way we think about PNS development, injury, and disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-MDCN-6 (01))
Program Officer
Owens, David F
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
Zip Code
Shimada, Issei S; Acar, Melih; Burgess, Rebecca J et al. (2017) Prdm16 is required for the maintenance of neural stem cells in the postnatal forebrain and their differentiation into ependymal cells. Genes Dev 31:1134-1146
Burgess, R J; Agathocleous, M; Morrison, S J (2014) Metabolic regulation of stem cell function. J Intern Med 276:12-24
Nishino, Jinsuke; Kim, Sunjung; Zhu, Yuan et al. (2013) A network of heterochronic genes including Imp1 regulates temporal changes in stem cell properties. Elife 2:e00924
Buchstaller, Johanna; McKeever, Paul E; Morrison, Sean J (2012) Tumorigenic cells are common in mouse MPNSTs but their frequency depends upon tumor genotype and assay conditions. Cancer Cell 21:240-52
Joseph, Nancy M; He, Shenghui; Quintana, Elsa et al. (2011) Enteric glia are multipotent in culture but primarily form glia in the adult rodent gut. J Clin Invest 121:3398-411
Nishino, Jinsuke; Saunders, Thomas L; Sagane, Koji et al. (2010) Lgi4 promotes the proliferation and differentiation of glial lineage cells throughout the developing peripheral nervous system. J Neurosci 30:15228-40
Chuikov, Sergei; Levi, Boaz P; Smith, Michael L et al. (2010) Prdm16 promotes stem cell maintenance in multiple tissues, partly by regulating oxidative stress. Nat Cell Biol 12:999-1006
Joseph, Nancy M; Mosher, Jack T; Buchstaller, Johanna et al. (2008) The loss of Nf1 transiently promotes self-renewal but not tumorigenesis by neural crest stem cells. Cancer Cell 13:129-40
Nishino, Jinsuke; Kim, Injune; Chada, Kiran et al. (2008) Hmga2 promotes neural stem cell self-renewal in young but not old mice by reducing p16Ink4a and p19Arf Expression. Cell 135:227-39
Mosher, Jack T; Yeager, Kelly J; Kruger, Genevieve M et al. (2007) Intrinsic differences among spatially distinct neural crest stem cells in terms of migratory properties, fate determination, and ability to colonize the enteric nervous system. Dev Biol 303:1-15

Showing the most recent 10 out of 19 publications