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Severe microcephaly induced by blockade of vasoactive intestinal peptide function in the primitive neuroepithelium of
P Gressens1, J M Hill, B Paindaveine
1Laboratory of Experimental Neuropathology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
Abstract:
Vasoactive intestinal peptide (VIP) has potent growth-related actions that influence cell mitosis, neuronal survival, and neurodifferentiation in cell culture. VIP can also produce dramatic growth in postimplantation mouse embryos in vitro, characterized by large increases in cell number. The goal of the present study was to assess the role of VIP on early nervous system development in vivo. Pregnant mice were treated with a specific antagonist to VIP. Prenatal administration of the antagonist early in development (E9-E11) produced severe microcephaly characterized by decreased embryonic brain weight with reduced DNA and protein content. The retardation of growth was disproportionally manifested in the brain compared with the body and was prevented by co-treatment with VIP. Identical treatment with the antagonist later in gestation had no detectable effect on embryonic growth. VIP receptors, which were restricted to the central nervous system during this stage of embryonic development, were increased in the neuroepithelium of antagonist-treated embryos while the number of cells in S-phase was significantly decreased. Thus, VIP regulates brain growth in vivo and inhibition of its action provides new insight into a molecular mechanism for microcephaly.
Insights
Vasoactive intestinal peptide (VIP) is crucial for early brain development. Blocking VIP in pregnant mice caused severe microcephaly in offspring, highlighting its role in fetal nervous system growth.
Area of Science:
- Neuroscience
- Developmental Biology
- Endocrinology
Background:
- Vasoactive intestinal peptide (VIP) exhibits growth-promoting effects on cells in vitro.
- VIP influences neuronal survival, mitosis, and differentiation, and promotes embryonic growth in vitro.
Purpose of the Study:
- To investigate the in vivo role of VIP in early nervous system development.
- To determine if VIP antagonism affects embryonic brain growth and development.
Main Methods:
- Pregnant mice were treated with a VIP-specific antagonist during early gestation (embryonic days 9-11).
- Embryonic growth, brain weight, DNA, and protein content were assessed.
- VIP receptor expression and cell proliferation (S-phase) were analyzed in neuroepithelial cells.
Main Results:
- Early prenatal administration of the VIP antagonist resulted in severe microcephaly, characterized by reduced embryonic brain weight, DNA, and protein.
- This growth retardation was specific to the brain and was prevented by co-administering VIP.
- Later gestation treatment with the antagonist had no observable effect on embryonic growth.
- VIP receptor expression increased, and S-phase cells decreased in the neuroepithelium of antagonist-treated embryos.
Conclusions:
- VIP plays a critical role in regulating embryonic brain growth in vivo.
- Inhibition of VIP signaling during early development is a potential molecular mechanism underlying microcephaly.
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