Canonical notch signaling directs the fate of differentiating neurocompetent progenitors in the mammalian olfactory epithelium

Daniel B. Herrick, Zhen Guo, Woochan Jang, Nikolai Schnittke, James E. Schwob

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

The adult olfactory epithelium (OE) has the remarkable capacity to regenerate fully both neurosensory and non-neuronal cell types after severe epithelial injury. Lifelong persistence of two stem cell populations supports OE regeneration when damaged: the horizontal basal cells (HBCs), dormant and held in reserve; and globose basal cells, a heterogeneous population most of which are actively dividing. Both populations regenerate all cell types of the OE after injury, but the mechanisms underlying neuronal versus non-neuronal lineage commitment after recruitment of the stem cell pools remains unknown. We used both retroviral transduction and mouse lines that permit conditional cell-specific genetic manipulation as well as the tracing of progeny to study the role of canonical Notch signaling in the determination of neuronal versus non-neuronal lineages in the regenerating adult OE. Excision of either Notch1 or Notch2 genes alone in HBCs did not alter progenitor fate during recovery from epithelial injury, whereas conditional knock-out of both Notch1 and Notch2 together, retroviral transduction of progenitors with a dominant-negative form of MAML (mastermind-like), or excision of the downstream cofactor RBPJ caused progeny to adopt a neuronal fate exclusively. Conversely, we show that overexpressing the Notch1-intracellular domain (N1ICD) either genetically or by transduction blocks neuronal differentiation completely. However, N1ICD overexpression requires both alleles of the canonical cofactor RBPJ to specify downstream lineage. Together, our results suggest that canonical RBPJ-dependent Notch signaling through redundant Notch1 and Notch2 receptors is both necessary and sufficient for determining neuronal versus non-neuronal differentiation in the regenerating adult OE.

Original languageEnglish (US)
Pages (from-to)5022-5037
Number of pages16
JournalJournal of Neuroscience
Volume38
Issue number21
DOIs
StatePublished - May 23 2018
Externally publishedYes

Keywords

  • Adult neurogenesis
  • Canonical
  • Chemical senses
  • Notch signaling
  • Notch1
  • RBPJ

ASJC Scopus subject areas

  • Neuroscience(all)

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