Mitotic sympathetic neuroblasts initiate axonal pathfinding in vivo

Abstract

Neuronal precursor proliferation and axodendritic outgrowth have been traditionally regarded as discrete and sequential developmental stages. However, we recently found that sympathetic neuroblasts in vitro often elaborate long neuritic processes before dividing. Furthermore, these "paramitotic" neurites were maintained during cell division and neuritic morphology was consistently preserved by daughter cells after mitosis. This inheritance of neuritic morphology in vitro raised the possibility that proliferating neuroblasts engage in axodendritic outgrowth. To determine whether mitotic superior cervical ganglion (SCG) neuroblasts are engaged in pathfinding in vivo, we have combined retrograde axonal tracing of efferent nerve trunks with bromodeoxyuridine (BrdU) labeling of cells in S-phase. In fact, about 13% of BrdU(+) cells were retrogradely labeled, indicating that mitotic neuroblasts often have extraganglionic axonal projections. Moreover, the presence of axons during S-phase was observed at two developmental ages (E15.5 and E16. 5), implicating an ongoing function of paramitotic axons during neuronal ontogeny. Using a calculation to account for experimental limitations, we estimate that virtually all mitotic SCG neuroblasts have direct access to extraganglionic signals during development. We conclude that mitotic neuronal precursors in vivo engage in pathfinding, raising the possibility that interaction of proliferating populations with distant signals actively coordinates cell division and neural connectivity.

Marrow Stromal Cells, Mitosis, and Neuronal Differentiation: Stem Cell and Precursor Functions

“…1B). Consequently, expression of neuronal morphological characters does not preclude cell division, consistent with observations of developing sympathetic neurons [25,26]. Additionally, PC12 cells expressing dysfunctional p53 display mature neurite formation while in S phase, demonstrating that mitotic arrest and functional maturation can be uncoupled in this cell line [27].…”

The location and phenotype of proliferating neural-crest-derived cells in the developing mouse gut

“…However, in developing sympathetic ganglia, cells express catecholamine synthetic enzymes and neuron-specific cytoskeletal proteins prior to exiting from the cell cycle (Rothman et al 1978;Stofer and Horn 1993). Furthermore, neurons in the superior cervical ganglion that project axons into the internal carotid nerve of the embryonic rat have been shown to undergo mitosis (Wolf et al 1999). Thus, sympathetic neuron precursors show some features of terminally differentiated neurons while continuing to divide.…”

The relationship of the birth date of rat sympathetic neurons to the target they innervate

“…One final consideration is that developing sympathetic neuroblasts continue to divide even after they start to express markers of a neuronal phenotype, including tyrosine hydroxylase (Rothman et al, 1978, 1980; Rohrer and Thoenen, 1987). There is also evidence that cell division can still occur even after axon extension (Wolf et al, 1999). While these properties make sympathetic neurons unusual among developing neurons, it is unclear how these properties might impact on the choice of target of an individual neuron.…”