Agrin-Lrp4-Ror2 signaling regulates adult hippocampal neurogenesis in mice

Abstract

Adult neurogenesis in the hippocampus may represent a form of plasticity in brain functions including mood, learning and memory. However, mechanisms underlying neural stem/progenitor cells (NSPCs) proliferation are not well understood. We found that Agrin, a factor critical for neuromuscular junction formation, is elevated in the hippocampus of mice that are stimulated by enriched environment (EE). Genetic deletion of the Agrn gene in excitatory neurons decreases NSPCs proliferation and increases depressive-like behavior. Low-density lipoprotein receptor-related protein 4 (Lrp4), a receptor for Agrin, is expressed in hippocampal NSPCs and its mutation blocked basal as well as EE-induced NSPCs proliferation and maturation of newborn neurons. Finally, we show that Lrp4 interacts with and activates receptor tyrosine kinase-like orphan receptor 2 (Ror2); and Ror2 mutation impairs NSPCs proliferation. Together, these observations identify a role of Agrin-Lrp4-Ror2 signaling for adult neurogenesis, uncovering previously unexpected functions of Agrin and Lrp4 in the brain.

E2F1‐Ror2 signaling mediates coordinated transcriptional regulation to promote G1/S phase transition in bFGF‐stimulated NIH/3T3 fibroblasts

“…22 In this case, Agrin stimulation increases tyrosine phosphorylation levels of Ror2 in neural stem cells. 22 Interestingly, Ror1 has been shown to be tyrosine phosphorylated by c-Met to promote Met-driven cancer cell proliferation, 49 indicating that tyrosine phosphorylation of Ror1 and Ror2 might be involved in regulating cell proliferation irrespective of Wnt5a. Further experiments will be required to unravel a possible involvement of tyrosine phosphorylation of Ror2 in regulating cell cycle progression of bFGF-stimulated cells.…”

“…Since Ror2 can mediate promotion of bFGF‐induced cell cycle progression in a Wnt5a‐independent manner (Figure S2, and (23)), it is important to clarify how Ror2 can be activated in bFGF‐stimulated cells. In adult hippocampal neural stem cells, Ror2 can be activated to promote their proliferation through the interaction with Lrp4 upon stimulation by Agrin, secreted from excitatory neurons . In this case, Agrin stimulation increases tyrosine phosphorylation levels of Ror2 in neural stem cells .…”

“…In adult hippocampal neural stem cells, Ror2 can be activated to promote their proliferation through the interaction with Lrp4 upon stimulation by Agrin, secreted from excitatory neurons . In this case, Agrin stimulation increases tyrosine phosphorylation levels of Ror2 in neural stem cells . Interestingly, Ror1 has been shown to be tyrosine phosphorylated by c‐Met to promote Met‐driven cancer cell proliferation, indicating that tyrosine phosphorylation of Ror1 and Ror2 might be involved in regulating cell proliferation irrespective of Wnt5a.…”

“…15,16 However, recent findings have revealed that Ror1 and/or Ror2 are expressed in the tissue stem cells not only during the embryonic development but also in adulthood. [17][18][19][20][21][22] In the adult skeletal muscles, Ror1 is expressed selectively in the adult muscle stem cells, known as satellite cells (SCs), and its expression in SCs can be further enhanced after muscle injury, leading to increased proliferation of SCs, thereby promoting regeneration of the damaged skeletal muscles. 20 In addition, expression of Ror2 is increased in reactive astrocytes that acquire stem cell-like properties in the injured brains, leading to increased proliferation of reactive astrocytes, thereby promoting repair following brain injury.…”

Poor Concordance of Floxed Sequence Recombination in Single Neural Stem Cells: Implications for Cell Autonomous Studies

“…In many studies, NSPC-targeted CreER T2 -lox systems are combined with a ubiquitously-expressed stop-floxed fluorescent reporter gene to confirm recombination in NSPCs (Sun et al, 2014;Kirby et al, 2015;Tannenholz et al, 2016). It is also common to use these fluorescent proteins more cell-specifically to investigate cell autonomous effects of recombination in the experimental gene of interest (Zimmermann et al, 2018;Zhou et al, 2018;Franz et al, 2019;Zhang et al, 2019).…”