Dsup16 in Neurogenesis

Project Details


Neural progenitor proliferation during embryonic neurogenesis needs to be tightly controlled, since it is fundamental for proper brain function, and a dysregulation in the numbers of forming neurons can cause a broad spectrum of brain disorders.

The dual-specificity phosphatase 16 (Dusp16), negatively regulate mitogen-activated protein kinases (MAPKs) and has never previously been implicated in brain development and disorders. In our joint project, we used Dusp16-deficient gene trap mice (Dusp16tp/tp), to study the role of Dusp16 in neurogenesis. Dusp16tp/tp developed fully-penetrant congenital obstructive hydrocephalus together with brain overgrowth. The midbrain aqueduct in Dusp16tp/tp mutants was obstructed during mid-gestation by an expansion of neural progenitors, and during later gestational stages by neurons resulting in a blockage of cerebrospinal fluid (CSF) outflow. In contrast, the roof plate and ependymal cells developed normally. We identified a delayed cell cycle exit of neural progenitors in Dusp16tp/tp mutants as a cause of progenitor overproliferation during midgestation. At later gestational stages, this expanded neural progenitor pool generated an increased number of neurons associated with enlarged brain volume.

Moreover, we found that the hippocampus fails to form in Dusp16tp/tp mutants, except for some small remnants. As cellular mechanism underlying this phenotype, we identified, in contrast to the neocortex and midbrain, a significant reduction of progenitor proliferation and cell cycle exit during midgestation in the hippocampal progenitor domain. Taken together, we found that Dusp16 plays a critical role in neurogenesis by balancing neural progenitor cell proliferation and neural differentiation and that this process is brain region specific.

Effective start/end date1/01/15 → …


  • United States-Israel Binational Science Foundation (BSF)


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