
Assistant Professor, Pediatrics
M_PEDS-CRITICAL CARE
+1 415 476-1034
The Arnold lab is interested in the communication between blood vessel and brain progenitor cells (radial glia) during brain development, and how this communication is altered in pediatric brain diseases, including congenital hydrocephalus, germinal matrix hemorrhage and cerebral palsy. To this end, out lab uses a combination of transcriptomic analysis and mouse genetics to discover novel roles for endothelial cells in brain and blood brain barrier development. We are particularly interested in the role of two factors wich appear to “couple” brain progenitor cell growth and differentiation with vascular development.
- We discovered that the integrin aVb8 on radial glia promotes both endothelial and microglia maturation by activating a “feed forward” TGFb circuit. Mice and humans with genetic deficits in this signaling pathway develop spontaneous brain hemorrhage, hydrocephalus and microglia activation, resulting in downstream neuromotor symptoms highly similar to humans with germinal matrix hemorrhage, congenital hydrocephalus and cerebral palsy.
- We developed a mouse model for a genetic form of congenital hydrocephalus called proliferative vasculopathy and hydranencephaly-hydrocephalus (PVHH) or Fowler Syndrome (OMIM 225790), and discovered that the heme transporter, Flvcr2, regulates endothelial heme and vascular sprouting in the brain. Our lab continues to investigate the role of integrins, TGFb, and unique transporters such as Flvcr2 in brain vascular development and human brain diseases.
Publications
Radial glia integrin avb8 regulates cell autonomous microglial TGFβ1 signaling that is necessary for microglial identity.
Nature communications
Dysregulation of FLVCR1a-dependent mitochondrial calcium handling in neural progenitors causes congenital hydrocephalus.
Cell reports. Medicine
Dynamic fibroblast-immune interactions shape wound healing after brain injury.
bioRxiv : the preprint server for biology
A comparative evaluation of the strengths and potential caveats of the microglial inducible CreER mouse models.
Cell reports
PTP1B mediates the inhibitory effect of MFGE8 on insulin signaling through the β5 integrin.
The Journal of biological chemistry
Structural and molecular basis of choline uptake into the brain by FLVCR2.
bioRxiv : the preprint server for biology
APOE4 impairs the microglial response in Alzheimer's disease by inducing TGFβ-mediated checkpoints.
Nature immunology
Radial glia promote microglial development through integrin α V β 8 -TGFβ1 signaling.
bioRxiv : the preprint server for biology
Finding the right tool: a comprehensive evaluation of microglial inducible cre mouse models.
bioRxiv : the preprint server for biology
The SARS-CoV-2 receptor ACE2 is expressed in mouse pericytes but not endothelial cells: Implications for COVID-19 vascular research.
Stem cell reports
Microglia are involved in the protection of memories formed during sleep deprivation.
Neurobiology of sleep and circadian rhythms
Bone Marrow-Derived Alk1 Mutant Endothelial Cells and Clonally Expanded Somatic Alk1 Mutant Endothelial Cells Contribute to the Development of Brain Arteriovenous Malformations in Mice.
Translational stroke research
Enrichment of Vascular Fragments from Mouse Embryonic Brains for Endothelial Cell Analysis.
Bio-protocol
CNS fibroblasts form a fibrotic scar in response to immune cell infiltration.
Nature neuroscience
Lack of Flvcr2 impairs brain angiogenesis without affecting the blood-brain barrier.
The Journal of clinical investigation
Disruption of the Extracellular Matrix Progressively Impairs Central Nervous System Vascular Maturation Downstream of ß-Catenin Signaling.
Arteriosclerosis, thrombosis, and vascular biology
Impaired aVß8 and TGFß signaling lead to microglial dysmaturation and neuromotor dysfunction.
The Journal of experimental medicine
Tissue Myeloid Progenitors Differentiate into Pericytes through TGF-ß Signaling in Developing Skin Vasculature.
Cell reports
Visualization of vascular mural cells in developing brain using genetically labeled transgenic reporter mice.
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
The avß1 integrin plays a critical in vivo role in tissue fibrosis.
Science translational medicine
LSR/angulin-1 is a tricellular tight junction protein involved in blood-brain barrier formation.
The Journal of cell biology
Excessive vascular sprouting underlies cerebral hemorrhage in mice lacking aVß8-TGFß signaling in the brain.
Development (Cambridge, England)
Mesangial cell avß8-integrin regulates glomerular capillary integrity and repair.
American journal of physiology. Renal physiology
Targeting of av integrin identifies a core molecular pathway that regulates fibrosis in several organs.
Nature medicine
Deletion of integrin-linked kinase from neural crest cells in mice results in aortic aneurysms and embryonic lethality.
Disease models & mechanisms
Transcriptional corepressors HIPK1 and HIPK2 control angiogenesis via TGF-ß-TAK1-dependent mechanism.
PLoS biology
Defective retinal vascular endothelial cell development as a consequence of impaired integrin aVß8-mediated activation of transforming growth factor-ß.
The Journal of neuroscience : the official journal of the Society for Neuroscience
Analysis of genomewide association signals for nonsyndromic cleft lip/palate in a Kenya African Cohort.
American journal of medical genetics. Part A
From death to recovery following hypoxia ischemia: if TGFbeta is a central regulator, is integrin beta8 the switch?
Neurotoxicity research
Distribution of orofacial clefts and frequent occurrence of an unusual cleft variant in the Rift Valley of Kenya.
The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association