Abstract
Boundary cap cells (BCC) are a transient, neural-crest-derived population found at the motor exit point (MEP) and dorsal root entry zone (DREZ) of the embryonic spinal cord. These cells contribute to the central/peripheral nervous system (CNS/PNS) boundary, and in their absence neurons and glia from the CNS migrate into the PNS. We found Netrin5 (Ntn5), a previously unstudied member of the netrin gene family, to be robustly expressed in BCC. We generated Ntn5 knockout mice and examined neurodevelopmental and BCC-related phenotypes. No abnormalities in cranial nerve guidance, dorsal root organization, or sensory projections were found. However, Ntn5 mutant embryos did have ectopic motor neurons (MNs) that migrated out of the ventral horn and into the motor roots. Previous studies have implicated semaphorin6A (Sema6A) in BCC signaling to plexinA2 (PlxnA2)/neuropilin2 (Nrp2) in MNs in restricting MN cell bodies to the ventral horn, particularly in the caudal spinal cord. In Ntn5 mutants, ectopic MNs are likely to be a different population, as more ectopias were found rostrally. Furthermore, ectopic MNs in Ntn5 mutants were not immunoreactive for NRP2. The netrin receptor deleted in colorectal cancer (DCC) is a potential receptor for NTN5 in MNs, as similar ectopic neurons were found in Dcc mutant mice, but not in mice deficient for other netrin receptors. Thus, Ntn5 is a novel netrin family member that is expressed in BCC, functioning to prevent MN migration out of the CNS.
Highlights
Neural crest cells migrate from the dorsal neural tube during vertebrate embryonic development and give rise to a variety of peripheral cell types, including the enteric and autonomic nervous systems, the neurons and glia of the sensory dorsal root ganglia (DRG), and myelinating Schwann cells
Boundary cap cells (BCC) are a transient neural crest-derived cell population that reside adjacent to the embryonic spinal cord at the point where sensory axons enter the spinal cord and at the point where motor axons exit the spinal cord
Ablation studies with diphtheria toxin revealed a paucity of TrkA-positive nociceptive neurons in the DRG, suggesting that BCC serve as progenitors that differentiate into these sensory neurons
Summary
Neural crest cells migrate from the dorsal neural tube during vertebrate embryonic development and give rise to a variety of peripheral cell types, including the enteric and autonomic nervous systems, the neurons and glia of the sensory dorsal root ganglia (DRG), and myelinating Schwann cells. Ablation studies with diphtheria toxin revealed a paucity of TrkA-positive nociceptive neurons in the DRG, suggesting that BCC serve as progenitors that differentiate into these sensory neurons. This is consistent with lineage tracing studies performed with Cre-reporters combined with Krox20Cre mice, which indicated that BCC can become satellite glia in the DRG and proximal Schwann cells in the dorsal root (Maro et al, 2004; Hjerling-Leffler et al, 2005; Aquino et al, 2006). BCC are a transient progenitor population of neural crest cells, they provide signals contributing to the demarcation of the central vs. peripheral nervous system (PNS)
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