Abstract
Bone morphogenetic proteins (BMPs) are a group of proteins that induce the formation of bone and the development of the nervous system. BMP-3b, also known as growth and differentiation factor 10, is a member of the BMPs that is highly expressed in the developing and adult brain. BMP-3b is therefore thought to play an important role in the brain even after physiological neurogenesis has completed. BMP-3b is induced in peri-infarct neurons in aged brains and is one of the most highly upregulated genes during the initiation of axonal sprouting. However, little is known about the role of BMP-3b in neonatal brain injury. In the present study, we aimed to describe the effects of BMP-3b gene depletion on neonatal hypoxic-ischemic encephalopathy, which frequently results in death or lifelong neurological disabilities, such as cerebral palsy and mental retardation. BMP-3b knockout and wild type mice were prepared at postnatal day 12. Mice of each genotype were divided into sham-surgery, mild hypoxia-ischemia (HI), and severe HI groups (n = 12–45). Mice in the HI groups were subjected to left common carotid artery ligation followed by 30 min (mild HI) or 50 min (severe HI) of systemic hypoxic insult. A battery of tests, including behavioral tests, was performed, and the brain was then removed and evaluated at 14 days after insult. Compared with wild type pups, BMP-3b knockout pups demonstrated the following characteristics. (1) The males exposed to severe HI had a strikingly higher mortality rate, and as many as 70% of the knockout pups but none of the wild type pups died; (2) significantly more hyperactive locomotion was observed in males exposed to severe HI; and (3) significantly more hyperactive rearing was observed in both males and females exposed to mild HI. However, BMP-3b gene depletion did not affect other parameters, such as cerebral blood flow, cylinder test and rotarod test performance, body weight gain, brain weight, spleen weight, and neuroanatomical injury. The results of this study suggest that BMP-3b may play a crucial role to survive in severe neonatal hypoxic-ischemic insult.
Highlights
Bone morphogenetic proteins (BMPs) form a subgroup in the transforming growth factor-β (TGF-β) superfamily and act as powerful morphogens that perform crucial roles during embryonic development [1, 2]
In animals subjected to the HI50 min insult, the mortality rate was 70% in male BMP-3b KO pups, and this was significantly higher than the rate observed in male wild type pups (0%)
BMP-3b gene depletion resulted in [1] a striking increase in mortality in males treated with severe HI insult, [2] significantly hyperactive locomotion in males treated with severe HI insult, and [3] significantly hyperactive rearing in males and females treated with mild HI insult
Summary
Bone morphogenetic proteins (BMPs) form a subgroup in the transforming growth factor-β (TGF-β) superfamily and act as powerful morphogens that perform crucial roles during embryonic development [1, 2]. They were first discovered as osteoinductive proteins, they were later recognized as critical regulators of nervous system development [2]. In 1996, we discovered a protein that was structurally similar to BMPs, especially BMP-3 We named it BMP3b [9, 10], and it is currently known as growth and differentiation factor 10 (GDF10) [11]. The role of BMP3b in injury to the developing brain has not yet been explored
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