Identification of an early subset of cerebellar nuclei neurons in mice
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Curated by eLife
eLife assessment
The authors identify a population of neurons with a specific complement of markers that originate in a distinct location from where cerebellar nuclear precursor cells have been thought to originate, that show distinct developmental properties. The discovery of a new germinal zone giving rise to a new population of CN neurons is an important finding, and it enriches our understanding of cerebellar development. The claims are supported by solid evidence and the authors use a wide range of technical approaches, including transgenic mice, that allow them to disentangle the influence of distinct developmental organizers.
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Abstract
Cerebellar nuclei (CN) neurons serve as the primary output of the cerebellum and originate from the cerebellar primordium at the early stages of cerebellar development. Employing various methodologies, we have characterized a specific subset of CN neurons that do not originate from the rhombic lip and the ventricular zone of the cerebellar primordium. Embryos were collected from timed pregnant mice at early stages of development and processed for immunohistochemistry (IHC), Western blotting, in situ hybridization (ISH), embryonic culture, DiI labeling, or flow cytometry analysis (FCM). Our findings indicate that a subset of CN neurons expressing α-synuclein (SNCA), OTX2, MEIS2, and p75NTR (NGFR) are located in the rostro-ventral (rv) region of the nuclear transitory zone (NTZ), while CN neurons derived from the rhombic lip are positioned in the caudo-dorsal (cd) area of the NTZ in the cerebellar primordium. Utilizing Otx2-GFP and Atoh1 -/- mice, we have determined that these cells do not originate from the germinal zone of the cerebellar primordium. These results suggest the existence of a novel extrinsic germinal zone for the cerebellar primordium, possibly the mesencephalon, from which early CN neurons originate.The cerebellum contains a variety of distinct neuronal populations, each playing a significant role in its function within the brain. This research demonstrates that a particular subset of cerebellar nuclei neurons originates from a previously unrecognized germinal zone specific to the cerebellar primordium, independently of Atoh1’s influence.
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eLife assessment
The authors identify a population of neurons with a specific complement of markers that originate in a distinct location from where cerebellar nuclear precursor cells have been thought to originate, that show distinct developmental properties. The discovery of a new germinal zone giving rise to a new population of CN neurons is an important finding, and it enriches our understanding of cerebellar development. The claims are supported by solid evidence and the authors use a wide range of technical approaches, including transgenic mice, that allow them to disentangle the influence of distinct developmental organizers.
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Reviewer #1 (Public Review):
Summary:
The authors are interested in the developmental origin of the neurons of the cerebellar nuclei. They identify a population of neurons with a specific complement of markers that originate in a distinct location from where cerebellar nuclear precursor cells have been thought to originate that show distinct developmental properties. The cerebellar nuclei have been well studied in recent years both to understand their development and through an evolutionary lens, which supports the importance of this study. The discovery of a new germinal zone giving rise to a new population of CN neurons is an exciting finding, and it enriches our understanding of cerebellar development, which has previously been quite straightforward, where cerebellar inhibitory cells arise from the ventricular zone and the excitatory …
Reviewer #1 (Public Review):
Summary:
The authors are interested in the developmental origin of the neurons of the cerebellar nuclei. They identify a population of neurons with a specific complement of markers that originate in a distinct location from where cerebellar nuclear precursor cells have been thought to originate that show distinct developmental properties. The cerebellar nuclei have been well studied in recent years both to understand their development and through an evolutionary lens, which supports the importance of this study. The discovery of a new germinal zone giving rise to a new population of CN neurons is an exciting finding, and it enriches our understanding of cerebellar development, which has previously been quite straightforward, where cerebellar inhibitory cells arise from the ventricular zone and the excitatory cells arise from the rhombic lip.
Strengths:
One of the strengths of the manuscript is that the authors use a wide range of technical approaches, including transgenic mice that allow them to disentangle the influence of distinct developmental organizers such as ATOH.
Their finding of a novel germinal zone and a novel population of CN neurons is important for developmental neuroscientists, and cerebellar neuroscientists.Weaknesses:
One important question raised by this work is what these newly identified cells eventually become in the adult cerebellum. Are they excitatory or inhibitory? Do they correspond to a novel cell type or perhaps one of the cell classes that have been recently identified in the cerebellum (e.g. Fujita et al., eLife, 2020)? Understanding this would significantly bolster the impact of this manuscript.
The major weakness of the manuscript is that it is written for a very specialized reader who has a strong background in cerebellar development, making it hard to read for a general audience. It's challenging to follow the logic of some of the experiments as well as to contextualize these findings in the field of cerebellar development.
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Reviewer #2 (Public Review):
Summary:
Canonically cerebellar neurons are derived from 2 primary germinal zones within the anterior hindbrain (dorsal rhombomere 1). This manuscript identifies an important, previously underappreciated origin for a subset of early cerebellar nuclei neurons - the dorsal mesencephalon. This is an exciting finding. While the conclusions are generally supported, several of the figure panels are of inferior quality and do not readily convey the results the authors assert.
Strengths:
The authors have identified a novel early population of cerebellar neurons with likely novel origin in the midbrain. They have used multiple assays to support their conclusions, including immunohistochemistry and in situ analyses of a number of markers of this population which appear to stream from the midbrain into the dorsal …
Reviewer #2 (Public Review):
Summary:
Canonically cerebellar neurons are derived from 2 primary germinal zones within the anterior hindbrain (dorsal rhombomere 1). This manuscript identifies an important, previously underappreciated origin for a subset of early cerebellar nuclei neurons - the dorsal mesencephalon. This is an exciting finding. While the conclusions are generally supported, several of the figure panels are of inferior quality and do not readily convey the results the authors assert.
Strengths:
The authors have identified a novel early population of cerebellar neurons with likely novel origin in the midbrain. They have used multiple assays to support their conclusions, including immunohistochemistry and in situ analyses of a number of markers of this population which appear to stream from the midbrain into the dorsal anterior cerebellar anlage.
The inclusion of Otx2-GFP short-term lineage analyses and analysis of Atoh1 -/- animals also provide considerable support for the midbrain origin of these neurons as streams of cells seem to emanate from the midbrain. However, without live imaging, there remains the possibility that these streams of cells are not actually migrating, and rather, gene expression is changing in static cells. Hence the authors have conducted midbrain diI labelling experiments of short-term and long-term cultured embryos showing di-labelled cells in the developing cerebellum. These studies confirm the migration of cells from the midbrain into the early cerebellum.
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