Abstract
The most ventral structure of the developing neural tube, the floor plate (FP), differs in neurogenic capacity along the neuraxis. The FP is largely non-neurogenic at the hindbrain and spinal cord levels, but generates large numbers of dopamine (mDA) neurons at the midbrain levels. Wnt1, and other Wnts are expressed in the ventral midbrain, and Wnt/beta catenin signaling can at least in part account for the difference in neurogenic capacity of the FP between midbrain and hindbrain levels. To further develop the hypothesis that canonical Wnt signaling promotes mDA specification and FP neurogenesis, we have generated a model wherein beta–catenin is conditionally stabilized throughout the FP. Here, we unambiguously show by fate mapping FP cells in this mutant, that the hindbrain and spinal cord FP are rendered highly neurogenic, producing large numbers of neurons. We reveal that a neurogenic hindbrain FP results in the altered settling pattern of neighboring precerebellar neuronal clusters. Moreover, in this mutant, mDA progenitor markers are induced throughout the rostrocaudal axis of the hindbrain FP, although TH+ mDA neurons are produced only in the rostral aspect of rhombomere (r)1. This is, at least in part, due to depressed Lmx1b levels by Wnt/beta catenin signaling; indeed, when Lmx1b levels are restored in this mutant, mDA are observed not only in rostral r1, but also at more caudal axial levels in the hindbrain, but not in the spinal cord. Taken together, these data elucidate both patterning and neurogenic functions of Wnt/beta catenin signaling in the FP, and thereby add to our understanding of the molecular logic of mDA specification and neurogenesis.
Highlights
The floor plate (FP) has long been recognized as a structure at the ventral midline of the central nervous system (CNS), conspicuously negative for neuronal elements [1,2]
The midbrain FP, at least partially loses expression of Otx2, Msx1, Ngn2 [4] and Lmx1a [4,18], maintains the expression of Shh, and thereby molecularly resembles the hindbrain FP [4]. These studies suggest that canonical Wnt signaling is necessary for midbrain dopamine neurons (mDA) specification and neurogenesis, it is possible that some of the effects seen in these studies are due to loss of integrity of adherens junctions [17]
In accordance with the notion that Wnt signaling is critical for mDA production, a recent study has used canonical Wntpromoting regimens to greatly improve mDA derived from human embryonic stem cells [19]
Summary
The floor plate (FP) has long been recognized as a structure at the ventral midline of the central nervous system (CNS), conspicuously negative for neuronal elements [1,2]. Wnt is expressed in the ventral midbrain but not ventral hindbrain or spinal cord [13,14,15] [16] and the Wnt null mutant has severely reduced numbers of mDA [15] Both FP-specific, and temporally controlled conditional ablation of beta–catenin results in the reduction of mDA neurogenesis [4,17,18]. In these mutants, the midbrain FP, at least partially loses expression of Otx, Msx, Ngn2 [4] and Lmx1a [4,18], maintains the expression of Shh, and thereby molecularly resembles the hindbrain FP [4]. In accordance with the notion that Wnt signaling is critical for mDA production, a recent study has used canonical Wntpromoting regimens to greatly improve mDA derived from human embryonic stem cells [19]
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