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Postmigratory neural crest cells expressing c-RET display restricted developmental and proliferative capacities
1Division of Biology, Howard Hughes Medical Institute, California Institute of Technology, Pasadena 91125, USA.
Abstract:
c-RET is an orphan receptor tyrosine kinase essential for enteric neurogenesis in mice and is involved in several human genetic disorders. RET is also one of the earliest surface markers expressed by postmigratory neural crest cells in the gut. We generated anti-RET monoclonal antibodies to isolate such cells. We find that RET+ cells are antigenically and functionally distinct from neural crest stem cells (NCSCs) characterized previously. Unlike NCSCs, which are RET- and MASH1-, most RET+ cells express MASH1. Moreover, unlike NCSCs, which are multipotent and have high proliferative capacity, many RET+ cells generate only neurons following a limited number of divisions. This behavior is observed even in the presence of glial growth factor, a polypeptide that suppresses neuronal and promotes glial differentiation by NCSCs. These data provide direct evidence for the existence of committed neuronal progenitor cells and support a model of neural crest lineage diversification by progressive restriction of developmental potential.
Insights
Researchers identified committed neuronal progenitor cells in the gut using anti-RET antibodies. These RET+ cells, distinct from neural crest stem cells, show restricted potential, advancing understanding of neural crest development.
Area of Science:
- Developmental biology
- Neuroscience
- Cell biology
Background:
- c-RET (receptor tyrosine kinase) is crucial for enteric neurogenesis and implicated in human genetic disorders.
- RET is an early surface marker on postmigratory neural crest cells in the gut.
- Neural crest stem cells (NCSCs) are multipotent with high proliferative capacity.
Purpose of the Study:
- To isolate and characterize RET-expressing cells in the developing gut.
- To determine if RET+ cells represent a distinct cell population from previously characterized NCSCs.
- To investigate the developmental potential and differentiation capacity of RET+ cells.
Main Methods:
- Generation of anti-RET monoclonal antibodies for cell isolation.
- Immunophenotypic analysis (e.g., MASH1 expression) of RET+ cells and NCSCs.
- Functional assays assessing proliferation and differentiation potential, including response to glial growth factor.
Main Results:
- RET+ cells were successfully isolated using anti-RET antibodies.
- RET+ cells are antigenically and functionally distinct from NCSCs.
- Most RET+ cells express MASH1, unlike NCSCs.
- RET+ cells exhibit limited proliferative capacity and a strong propensity for neuronal differentiation, even in the presence of glial growth factor.
Conclusions:
- Direct evidence supports the existence of committed neuronal progenitor cells within the developing gut.
- These findings support a model of neural crest lineage diversification through progressive restriction of developmental potential.
- The study identifies RET as a key marker for a specific neuronal progenitor population.