Related Experiment Video
Updated: Jun 19, 2025
Using Zebrafish Larvae to Study the Pathological Consequences of Hemorrhagic Stroke
Published on: June 5, 2019
Fibrinogen inhibits sonic hedgehog signaling and impairs neonatal cerebellar development after blood-brain barrier
Olivia Weaver1,2,3, Dawn Gano1,4, Yungui Zhou2,3
1Department of Pediatrics, University of California San Francisco, San Francisco, CA 94158.
Insights
Fibrinogen, a blood protein, harms neonatal cerebellar development after brain bleeds in preterm infants. Depleting fibrinogen protects against brain injury and preserves cerebellar growth.
Area of Science:
- Neuroscience
- Developmental Biology
- Neonatal Medicine
Background:
- Cerebellar injury in preterm infants with central nervous system (CNS) hemorrhage leads to long-term neurological deficits and increased autism risk.
- The specific blood-induced pathways affecting cerebellar development are not well understood, hindering treatment development for neonatal neurovascular damage.
- Current treatments lack targeted approaches to counteract the detrimental effects of blood on the developing cerebellum.
Purpose of the Study:
- To investigate the role of fibrinogen in impairing neonatal cerebellar development following CNS hemorrhage.
- To elucidate the mechanisms by which blood components, specifically fibrinogen, affect cerebellar growth and neurogenesis.
- To identify potential therapeutic targets for mitigating brain injury in preterm infants.
Main Methods:
- Longitudinal magnetic resonance imaging (MRI) in preterm infants to correlate cerebellar bleeds with growth.
- Utilized inflammatory and hemorrhagic mouse models of neonatal cerebellar injury.
- Assessed the impact of fibrinogen on innate immune activation, neurogenesis, and sonic hedgehog (SHH) signaling in the cerebellum.
- Investigated the effects of genetic fibrinogen depletion on cerebellar development.
Main Results:
- Cerebellar bleeds were identified as the most critical factor for poor cerebellar growth in preterm infants.
- Fibrinogen was found to increase innate immune activation and impede neurogenesis in the developing cerebellum.
- Fibrinogen inhibited SHH signaling, a key pathway for cerebellar granule neuron progenitor (CGNP) proliferation, and disrupted cerebellar growth.
- Genetic depletion of fibrinogen reduced neuroinflammation, enhanced CGNP proliferation, and preserved cerebellar development post-injury.
Conclusions:
- Fibrinogen plays a central role in hindering neonatal cerebellar development after CNS hemorrhage.
- Fibrinogen disrupts the balance of SHH signaling within the cerebellar neurovascular niche.
- Fibrinogen emerges as a potential therapeutic target to prevent or reduce developmental brain injury in preterm infants.
Abstract:
Cerebellar injury in preterm infants with central nervous system (CNS) hemorrhage results in lasting neurological deficits and an increased risk of autism. The impact of blood-induced pathways on cerebellar development remains largely unknown, so no specific treatments have been developed to counteract the harmful effects of blood after neurovascular damage in preterm infants. Here, we show that fibrinogen, a blood-clotting protein, plays a central role in impairing neonatal cerebellar development. Longitudinal MRI of preterm infants revealed that cerebellar bleeds were the most critical factor associated with poor cerebellar growth. Using inflammatory and hemorrhagic mouse models of neonatal cerebellar injury, we found that fibrinogen increased innate immune activation and impeded neurogenesis in the developing cerebellum. Fibrinogen inhibited sonic hedgehog (SHH) signaling, the main mitogenic pathway in cerebellar granule neuron progenitors (CGNPs), and was sufficient to disrupt cerebellar growth. Genetic fibrinogen depletion attenuated neuroinflammation, promoted CGNP proliferation, and preserved normal cerebellar development after neurovascular damage. Our findings suggest that fibrinogen alters the balance of SHH signaling in the neurovascular niche and may serve as a therapeutic target to mitigate developmental brain injury after CNS hemorrhage.
