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Targeted deletion of Hand2 in enteric neural precursor cells affects its functions in neurogenesis, neurotransmitter specification and gangliogenesis, causing functional aganglionosis
Copyright policy )Targeted deletion of Hand2 in enteric neural precursor cells affects its functions in neurogenesis, neurotransmitter specification and gangliogenesis, causing functional aganglionosis
Targeted deletion of the bHLH DNA-binding protein Hand2 in the neural crest, impacts development of the enteric nervous system (ENS), possibly by regulating the transition from neural precursor cell to neuron. We tested this hypothesis by targeting Hand2 deletion in nestin-expressing neural precursor (NEP) cells. The mutant mice showed abnormal ENS development, resulting in lethal neurogenic pseudo-obstruction. Neurogenesis of neurons derived from NEP cells identified a second nestin non-expressing neural precursor (NNEP) cell in the ENS. There was substantial compensation for the loss of neurons derived from the NEP pool by the NNEP pool but this was insufficient to abrogate the negative impact of Hand2 deletion. Hand2-mediated regulation of proliferation affected both neural precursor and neuron numbers. Differentiation of glial cells derived from the NEP cells was significantly decreased with no compensation from the NNEP pool of cells. Our data indicate differential developmental potential of NEPs and NNEPs; NNEPs preferentially differentiate as neurons, whereas NEPs give rise to both neurons and glial cells. Deletion of Hand2 also resulted in complete loss of NOS and VIP and a significant decrease in expression of choline acetyltransferase and calretinin, demonstrating a role for Hand2 in neurotransmitter specification and/or expression. Loss of Hand2 resulted in a marked disruption of the developing neural network, exemplified by lack of a myenteric plexus and extensive overgrowth of fibers. Thus, Hand2 is essential for neurogenesis, neurotransmitter specification and neural network patterning in the developing ENS.
- University System of Ohio United States
- University of Toledo United States
- University of Toledo Health Science Campus United States
Medical Subject Headings: animal structures nervous system embryonic structures
Microsoft Academic Graph classification: Precursor cell medicine Genetics biology Neurogenesis Neural crest Nestin Cell biology medicine.anatomical_structure biology.protein Enteric nervous system Neuron Stem cell HAND2
Neurogenesis, Nerve Tissue Proteins, Enteric Nervous System, Nestin, Mice, Intermediate Filament Proteins, Basic Helix-Loop-Helix Transcription Factors, Animals, Ganglia, Autonomic, Molecular Biology, Research Articles, Cell Proliferation, Mice, Knockout, Neurons, Neurotransmitter Agents, Stem Cells, Embryo, Mammalian, Intestines, Gene Deletion, Developmental Biology
Neurogenesis, Nerve Tissue Proteins, Enteric Nervous System, Nestin, Mice, Intermediate Filament Proteins, Basic Helix-Loop-Helix Transcription Factors, Animals, Ganglia, Autonomic, Molecular Biology, Research Articles, Cell Proliferation, Mice, Knockout, Neurons, Neurotransmitter Agents, Stem Cells, Embryo, Mammalian, Intestines, Gene Deletion, Developmental Biology
Medical Subject Headings: animal structures nervous system embryonic structures
Microsoft Academic Graph classification: Precursor cell medicine Genetics biology Neurogenesis Neural crest Nestin Cell biology medicine.anatomical_structure biology.protein Enteric nervous system Neuron Stem cell HAND2
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Barlow, A. J., Wallace, A. S., Thapar, N. and Burns, A. J. (2008). Critical numbers of neural crest cells are required in the pathways from the neural tube to the foregut to ensure complete enteric nervous system formation. Development 135, 1681-1691.
Barron, F., Woods, C., Kuhn, K., Bishop, J., Howard, M. J. and Clouthier, D. E. (2011). Downregulation of Dlx5 and Dlx6 expression by Hand2 is essential for initiation of tongue morphogenesis. Development 138, 2249-2259.
Binder, B. J., Landman, K. A., Simpson, M. J., Mariani, M. and Newgreen, D. F. (2008). Modeling proliferative tissue growth; a general approach and an avian case study. Phys. Rev. E Stat. Nonlin. Soft Matter Phys. 78, 031912.
Bornstein, J. C., Costa, M. and Grider, J. R. (2006). Enteric motor and interneuronal circuits controlling motility. Neurogastroenterol. Motil. 16, 34-38.
Brewer, S., Feng, W., Huang, J., Sullivan, S. and Williams, T. (2004). Wnt1- Cre-mediated deletion of AP-2 alpha causes multiple neural crest-related defects. Dev. Biol. 267, 135-152.
Burns, A. J. and Le Douarin, N. M. (2000). Enteric nervous system development: analysis of the selective developmental potentialities of vagal and sacral neural crest cells using quail-chick chimeras. Anat. Rec. 262, 16-28.
Burns, A. J., Roberts, R. R., Bornstein, J. C. and Young, H. M. (2009). Development of the enteric nervous system and its role in intestinal motility during fetal and early postnatal stages. Semin. Pediatr. Surg. 18, 196-205.
Conner, P. J., Focke, P. J., Noden, D. M. and Epstein, M. L. (2003). Appearance of neurons and glia with respect to the wavefront during colonization of the avian gut by neural crest cells. Dev. Dyn. 226, 91-98. [OpenAIRE]
D'Autrèaux, F. D., Morikawa, Y., Cserjesi, P. and Gershon, M. D. (2007). Hand2 is necessary for terminal differentiation of enteric neurons from crestderived precursors but not for their migration into the gut or for formation of glia. Development 134, 2237-2249. [OpenAIRE]
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).49 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 10% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 10% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 10% citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).49 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 10% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 10% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 10%
Citations provided by BIP!Popularity provided by BIP!- University System of Ohio United States
- University of Toledo United States
- University of Toledo Health Science Campus United States
Targeted deletion of the bHLH DNA-binding protein Hand2 in the neural crest, impacts development of the enteric nervous system (ENS), possibly by regulating the transition from neural precursor cell to neuron. We tested this hypothesis by targeting Hand2 deletion in nestin-expressing neural precursor (NEP) cells. The mutant mice showed abnormal ENS development, resulting in lethal neurogenic pseudo-obstruction. Neurogenesis of neurons derived from NEP cells identified a second nestin non-expressing neural precursor (NNEP) cell in the ENS. There was substantial compensation for the loss of neurons derived from the NEP pool by the NNEP pool but this was insufficient to abrogate the negative impact of Hand2 deletion. Hand2-mediated regulation of proliferation affected both neural precursor and neuron numbers. Differentiation of glial cells derived from the NEP cells was significantly decreased with no compensation from the NNEP pool of cells. Our data indicate differential developmental potential of NEPs and NNEPs; NNEPs preferentially differentiate as neurons, whereas NEPs give rise to both neurons and glial cells. Deletion of Hand2 also resulted in complete loss of NOS and VIP and a significant decrease in expression of choline acetyltransferase and calretinin, demonstrating a role for Hand2 in neurotransmitter specification and/or expression. Loss of Hand2 resulted in a marked disruption of the developing neural network, exemplified by lack of a myenteric plexus and extensive overgrowth of fibers. Thus, Hand2 is essential for neurogenesis, neurotransmitter specification and neural network patterning in the developing ENS.