and myelination


Starting with the analysis of two mutants (st49 and st63) from our genetic screen

(Pogoda et al. 2006, Developmental Biology, 298: 118-131), we discovered that

the adhesion G protein coupled receptor Gpr126 is required for Schwann cells to

initiate myelination (Monk et al. 2009, Science 325: 1402-1405). In gpr126 mutants,

Schwann cells arrest just before the onset of myelination.  Elevation of cAMP restores

myelination in gpr126 mutants.  After the early signaling defect is bypassed by

transient elevation of cAMP, Schwann cells in gpr126 mutants can form a mature

myelin sheath, and maintain it for months (Glenn and Talbot, 2013, Development

140: 3167-3175).  Thus our analysis indicates that Gpr126 signaling is required

specifically at the onset of myelination.


The function of Gpr126 in myelination is widely conserved among vertebrates, as

we showed by analyzing Gpr126 mutant mice (Monk et al. 2011, Development

138: 2673-2680) and, as part of a collaborative study, mutations in GPR126 in

human patients (Ravenscroft et al. 2015, American Journal of Human Genetics).


Current experiments are focused on understanding the Gpr126 signaling pathway

and its interaction other factors that regulate Schwann cell development and

myelination.  We are working to determine if type IV collagen, a component of the

Schwann cell extracellular matrix that can bind and activate Gpr126 in cultured

cells (Paavola et al. 2014 Science Signaling 7: ra76), is important for Gpr126

signaling and myelination in vivo.  In addition, we are investigating how Gpr126

activity intersects with Neuregulin signaling to control Schwann cell myelination.

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Neuregulin and Schwann

cell development


Through mutational analysis in zebrafish, we discovered that ErbB receptor tyrosine

kinases are essential for directed migration of Schwann cells in growing nerves

(Lyons et al. 2005, Current Biology 15: 513-524). Previous work in mammals has

indicated that ErbB receptors and their Neuregulin ligands control many aspects

of Schwann cell development, including proliferation and myelination. We found

that zebrafish erbb mutants have defects in Schwann cell migration, in addition to

proliferation and myelination. By applying a drug that blocks ErbB signaling after the

start of migration, we showed that ErbB signaling is required for directed migration

of Schwann cells, not simply for their motility.  In addition, we found that ErbB

signaling is required for Schwann cells to extend processes into bundles of axons

during radial sorting, the process that pairs Schwann cells with the axons segments

they will myelinate (Raphael et al. 2005, Glia 59: 1047-1055).


Our mutational studies and other experiments provide evidence that Neuregulin

(Nrg) type III signals are essential guidance cues for migrating Schwann cells

(Perlin et al. 2011, Development 138: 4639-4648).  By controlling Schwann cell

proliferation and migration, Nrg1-type III ensures that Schwann cells are present

in the proper numbers and proper places to myelinate the appropriate axonal

segments.  Our current experiments are focused on understanding how Nrg-ErbB

signaling is regulated to direct Schwann cell migration and on analyzing the




Kif1b and mbp

RNA localization


In the CNS of mammals and zebrafish, mRNAs encoding myelin basic proteins

(Mbp) and a small number of other structural components of myelin are localized to

processes of myelinating oligodendrocytes. Until recently, the role of specific myelin

mRNA localization in oligodendrocyte differentiation was not understood.  We have

discovered that mutation of kif1b, which encodes a kinesin motor, causes defects

in mbp mRNA localization in oligodendrocytes (Lyons et al. 2009, Nature Genetics

41: 854-858). In kif1b mutants, mbp mRNA is present in oligodendrocyte cell

bodies, but not in myelinating processes. Mbp protein is present in the processes

of mutant oligodendrocytes despite the lack of mbp mRNA. We are working to

determine if the Kif1b motor acts directly to transport mRNA cargo into myelinating



The finding that mbp mRNA is mislocalized in kif1b mutants provided the opportunity

to investigate the role of mRNA localization in oligodendrocytes. In kif1b mutants,

long stretches of compact myelin-like membranes were observed surrounding

neuronal cell bodies and in processes that did not ensheath axons. Mbp protein is

present at abnormally high levels in oligodendrocyte cell bodies of kif1b mutants,

suggesting that mislocalized myelin proteins contribute to aberrant membrane

compaction in kif1b mutants. According to this model, the role of mRNA localization

in oligodendrocytes is to restrict the localization of Mbp and thereby prevent the

deleterious action of myelin proteins in other parts of the cell.


In ongoing experiments, we have defined a region on the 3’ UTR of mbp mRNA

that is sufficient to localize a heterologous mRNA to myelinating processes.  We

are using genome editing methods to delete this localization element and other

sequences to define regions of the mbp mRNA that are required for its localization


Inflammation and

microglia development


Through mutational analysis in zebrafish, we discovered that the noncanonical NOD

-like receptor (NLR) Nlrc3-like is essential for formation of microglia (Shiau et al.,

2013, Cell Reports 5: 1342-1352). Although most NLRs trigger inflammatory

signaling, we found that Nlrc3-like acts cell autonomously in microglia precursor

cells to suppress unwarranted inflammation in the absence of infection. In nlrc3-

like mutants, primitive macrophages initiate a systemic inflammatory response with

increased proinflammatory cytokines and actively aggregate instead of migrating into

the brain to form microglia.  In addition, neutrophils infiltrate the brain in nlrc3-like

mutants, whereas these immune cells are excluded from the CNS of wildtype

siblings. Together, these results demonstrate that Nlrc3-like prevents inappropriate

macrophage activation, thereby allowing normal microglial development. Our results

support the model that Nlrc3-like may regulate the inflammasome and other

inflammatory pathways is to prevent the initiation of inappropriate inflammatory

responses.  Mechanistic investigation of Nlrc3-like will advance the understanding




specification and migration





Microglia and Cell Biology of



Microglia are resident macrophages of the CNS that are essential for phagocytosis of apoptotic neurons and weak synapses during development. Using forward and reverse genetic approaches, we discovered that RagA and Lamtor4, two components of the Rag-Ragulator complex, are essential regulators of lysosomes in microglia (Shen et al. 2016, Cell Reports 14: 547-559). In zebrafish lacking RagA function, microglia exhibit an expanded lysosomal compartment, but they are unable to properly digest apoptotic neuronal debris. Our analysis reveals an essential role of the Rag-Ragulator complex in proper lysosome function and phagocytic flux in microglia. We are currently working to define the mechanisms by which the Rag-Ragulator complex regulates lysosomes, and to define the function of RagA in other cell types. In a genetic screen, we uncovered an essential role for the phosphate exporter xpr1b in microglia and other tissue-resident macrophages (Meireles et al. 2014, Cell Reports 6: 1659-1667). xpr1b mutants lack microglia and display an osteopetrotic phenotype characteristic of defects in osteoclast function. Our genetic analysis in zebrafish provides strong evidence that Xpr1b acts cell autonomously in the macrophage precursor population and has a unique and specific function in specialized tissue macrophages, including microglia and osteoclasts. Our hypothesis is that these phagocytic cells require Xpr1b to prevent harmful levels of phosphate from accumulating as they engulf apoptotic neurons, bone, and other debris rich in phosphate.     back to top



talbot lab.  stanford school of medicine.  copyright © 2015.  all rights reserved.