Mutations in embryonic blood-cell precursors called erythro-myeloid progenitors cause abnormal activation of their descendants — immune cells called microglia — leading to neurodegeneration in mice. See Letter p.389
Haematopoietic stem cells in the embryo can give rise to all lineages of blood cell, but not all blood cells derive from haematopoietic stem cells (HSCs). For instance, erythro-myeloid progenitors (EMPs) emerge in an embryonic structure called the yolk sac before HSCs exist, and give rise to diverse lineages of blood cell that are crucial for survival1. In addition to their role in development, EMPs give rise to a long-lived population of adult immune cells of the myeloid lineage, called EMP-derived tissue macrophages2,3,4. These cells are found in many adult tissues, including the brain, heart and skin, and can co-exist with HSC-derived macrophages — a fact that has led some researchers to speculate that these two embryonic cell populations have different roles in adult disease5,6. On page 389, Mass et al.7 provide definitive support for this hypothesis.
Histiocytoses are a group of diseases characterized by an abundance of macrophages or immune cells called dendritic cells8. They can affect diverse organs, including the bone, skin and spleen. Central nervous system (CNS) involvement is rare, but has a poor prognosis8. A common cause of histiocytoses8 is a single amino-acid substitution in the gene BRAF. The resulting mutation (dubbed BRAF600) causes hyperactive RAS-pathway signalling that leads to excessive proliferation of cells. Interestingly, although this mutation is found in hairy cell leukaemia (a cancer of white blood cells called B cells), it has not been detected in myeloid leukaemias9,10, which involve myeloid cells. The differing frequency of BRAF600 mutations in histiocytoses and myeloid leukaemias suggests that, even though both these blood-cell disorders involve myeloid cells, they might have different cellular and developmental origins.
To investigate the possibility that histiocytoses are caused by EMP-derived cells, Mass et al. generated genetically engineered mice in which embryonic EMPs alone harboured the Braf600 mutation. By monitoring Braf600-expressing cells using a fluorescent marker, the authors confirmed that the mutation was not present in HSCs. Mice with Braf600-expressing EMPs showed no evidence of disease prenatally or immediately after birth. Nevertheless, mutant EMPs gave rise to expanded populations of macrophages — including those in the CNS, known as microglia — indicative of a histiocytosis. Mutant microglia in one-month-old mice proliferated more and underwent programmed cell death less often than did EMP-derived microglia in control animals. The mutant mice subsequently developed progressive neurological impairment, characterized by muscle weakness, impaired motor coordination, loss of reflexes and, ultimately, limb paralysis.
Mass et al. observed that mutant microglia had a rounded shape indicative of activation. They found hallmarks of neurodegeneration in nearby cells: deposition of amyloid precursor protein; loss of neurons and marked damage to the protective myelin sheath around them; and an increase in the numbers of neuron-supporting astrocyte cells (Fig. 1). These findings suggest that factors secreted from activated mutant microglia were driving disease. Indeed, the authors performed a gene-expression analysis that confirmed the upregulation of several markers of neurodegeneration in the CNS of mutant mice. These include pro-inflammatory mediators such as interleukin-1β (IL-1β) and IL-17α, growth factors that signal through the RAS pathway, and proteins associated with the extracellular matrix around cells.
The researchers are the first to prove that embryonic mutations in EMPs can cause neurodegenerative disease after birth in mice. Their conclusions emphasize that developmental origins should be considered when studying disorders caused by blood cells. Furthermore, the authors highlight the different responses of distinct blood-cell lineages to cancer-causing mutations. Whereas Braf600 expression in EMPs caused neurodegeneration, the same mutation expressed in HSCs in mice caused prenatal lethality or myeloid-cell tumours in diverse tissues, including the spleen, lungs and bone marrow. This finding suggests that the EMP lineage might be resistant to cancerous transformation. Further work will be needed to identify the properties of EMPs that confer this resistance — knowledge that could potentially be used to evoke similar protective signals in HSC-derived blood cells.
A crucial next step in understanding how EMP-derived cells cause neurodegeneration will be to determine the precise contribution of aberrant developmental cues to this process. For instance, would postnatal Braf600 mutations in microglia also result in progressive ataxia and limb weakness, or are these symptoms dependent on the prenatal seeding of the CNS with mutant microglia? Clarifying the developmental stage at which microglia are susceptible to the effects of mutations will refine our understanding of disease pathogenesis and help to identify potential therapeutic windows for intervention.
“The authors’ conclusions emphasize that developmental origins should be considered when studying disorders caused by blood cells.”
Mass and colleagues' findings could help in the diagnosis of neurodegenerative disorders caused by EMPs. They identified more than 8,000 genes that were differentially expressed between mutant and control microglia. Further analysis of this gene set might enable the identification of a unique gene-expression signature for embryonically derived neurodegenerative disorders. The authors also demonstrate that, in addition to causing defects in the CNS of their mice, mutant EMPs gave rise to abnormal macrophages in the spleen, liver and lung. This suggests that it might be possible to collect macrophage samples from more-easily-accessible, non-CNS tissues to look for biomarkers when diagnosing microglia-related disease.
EMPs are a remarkable and under-explored contributor to neurodegenerative disorders. The challenge ahead will be to translate this discovery into treatments. Mass and colleagues' findings hint at two possible strategies. First, targeted therapy against key signalling molecules might delay the onset of symptoms. The authors demonstrated that blocking hyperactive RAS signalling using a BRAFV600E inhibitor could delay the onset of neurological defects in their mutant mice. In addition, they analysed several CNS samples from patients who had histiocytoses, and found notable similarities with their model mice, including microglial activation, hyperactive RAS signalling and overexpression of pro-inflammatory signalling molecules, including IL-1β and IL-17α. In support of this strategy, some patients with histiocytic CNS diseases have shown promising responses to BRAFV600E inhibition11,12. It is to be hoped that future controlled studies will assess the efficacy of this approach and identify those patients who might benefit.
A second and more intriguing strategy would be to further explore differences between EMPs and HSCs that express BRAFV600E. This approach would draw on the depth of our understanding of blood-cell development to identify molecular targets that are specific to EMPs. Such knowledge could lead to highly specific, HSC-sparing therapies whose mechanism of action is restricted to EMPs or microglia. Footnote 1
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