Motor neurons control blood vessel patterning in the developing spinal cord

Patricia Himmels; Isidora Paredes; Heike Adler; Andromachi Karakatsani; Robert Luck; Hugo H Marti; Olga Ermakova; Eugen Rempel; Esther T Stoeckli; Carmen Ruiz de Almodóvar

doi:10.1038/ncomms14583

Motor neurons control blood vessel patterning in the developing spinal cord

Nat Commun. 2017 Mar 6:8:14583. doi: 10.1038/ncomms14583.

Authors

Patricia Himmels^{1

2}, Isidora Paredes^{1

2}, Heike Adler^{1

2}, Andromachi Karakatsani^{1

2}, Robert Luck^{1

2}, Hugo H Marti³, Olga Ermakova⁴, Eugen Rempel⁴, Esther T Stoeckli⁵, Carmen Ruiz de Almodóvar^{1

2}

Affiliations

¹ Biochemistry Center, Heidelberg University, 69120 Heidelberg, Germany.
² Interdisciplinary Center for Neurosciences, Heidelberg University, 69120 Heidelberg, Germany.
³ Institute of Physiology and Pathophysiology, Heidelberg University, 69120 Heidelberg, Germany.
⁴ Department of Stem Cell Biology, Centre for Organismal Studies, Heidelberg University, 69120 Heidelberg, Germany.
⁵ Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.

Abstract

Formation of a precise vascular network within the central nervous system is of critical importance to assure delivery of oxygen and nutrients and for accurate functionality of neuronal networks. Vascularization of the spinal cord is a highly stereotypical process. However, the guidance cues controlling blood vessel patterning in this organ remain largely unknown. Here we describe a new neuro-vascular communication mechanism that controls vessel guidance in the developing spinal cord. We show that motor neuron columns remain avascular during a developmental time window, despite expressing high levels of the pro-angiogenic vascular endothelial growth factor (VEGF). We describe that motor neurons express the VEGF trapping receptor sFlt1 via a Neuropilin-1-dependent mechanism. Using a VEGF gain-of-function approach in mice and a motor neuron-specific sFlt1 loss-of-function approach in chicken, we show that motor neurons control blood vessel patterning by an autocrine mechanism that titrates motor neuron-derived VEGF via their own expression of sFlt1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autocrine Communication
Blood Vessels / growth & development
Blood Vessels / metabolism*
Body Patterning / genetics
Chickens
Embryo, Mammalian
Gene Expression Regulation, Developmental
Genes, Reporter
Green Fluorescent Proteins / genetics
Green Fluorescent Proteins / metabolism
Mice
Mice, Inbred C57BL
Mice, Transgenic
Motor Neurons / cytology
Motor Neurons / metabolism*
Neovascularization, Physiologic / genetics*
Neuropilin-1 / genetics
Neuropilin-1 / metabolism
Signal Transduction
Spinal Cord / blood supply
Spinal Cord / growth & development
Spinal Cord / metabolism*
Vascular Endothelial Growth Factor A / genetics*
Vascular Endothelial Growth Factor A / metabolism
Vascular Endothelial Growth Factor Receptor-1 / genetics*
Vascular Endothelial Growth Factor Receptor-1 / metabolism

Substances

Vascular Endothelial Growth Factor A
enhanced green fluorescent protein
vascular endothelial growth factor A, mouse
Neuropilin-1
Green Fluorescent Proteins
Flt1 protein, mouse
Vascular Endothelial Growth Factor Receptor-1