Dusp16 Deficiency Causes Congenital Obstructive Hydrocephalus and Brain Overgrowth by Expansion of the Neural Progenitor Pool

Abstract

Hydrocephalus can occur in children alone or in combination with other neurodevelopmental disorders that are often associated with brain overgrowth. Despite the severity of these disorders, the molecular and cellular mechanisms underlying these pathologies and their comorbidity are poorly understood. Here, we studied the consequences of genetically inactivating in mice dual-specificity phosphatase 16 (Dusp16), which is known to negatively regulate mitogen-activated protein kinases (MAPKs) and which has never previously been implicated in brain development and disorders. Mouse mutants lacking a functional Dusp16 gene (Dusp16−/−) developed fully-penetrant congenital obstructive hydrocephalus together with brain overgrowth. The midbrain aqueduct in Dusp16−/− 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 Dusp16−/− mutants as a cause of progenitor overproliferation during mid-gestation. At later gestational stages, this expanded neural progenitor pool generated an increased number of neurons associated with enlarged brain volume. Taken together, we found that Dusp16 plays a critical role in neurogenesis by balancing neural progenitor cell proliferation and neural differentiation. Moreover our results suggest that a lack of functional Dusp16 could play a central role in the molecular mechanisms linking brain overgrowth and hydrocephalus.

Dual-specificity MAP kinase phosphatases in health and disease

“…This was secondary to blockage of the midbrain aqueduct by the expansion of neural progenitor cells, eventually preventing the outflow of cerebrospinal fluid. Interestingly only an increase in cells staining positively for phospho-p38 was observed in the affected regions of the CNS indicating that this MAPK, rather than ERK or JNK could be the relevant target [ 199 ].…”

From man to fly – convergent evidence links FBXO25 to ADHD and comorbid psychiatric phenotypes

“…Indeed, WES revealed an additional de novo frameshift variant in the DUSP16 gene in the index patient, who also showed additional somatic features, anxiety disorder, and psychiatric episodes at very young age. A recent study reported that Dusp16 plays a critical role in neurogenesis by balancing neural progenitor cell proliferation and neural differentiation (Zega et al, ). Moreover, mouse mutants lacking a functional Dusp16 gene developed fully‐penetrant congenital obstructive hydrocephalus together with brain overgrowth (Zega et al, ).…”

“…A recent study reported that Dusp16 plays a critical role in neurogenesis by balancing neural progenitor cell proliferation and neural differentiation (Zega et al, ). Moreover, mouse mutants lacking a functional Dusp16 gene developed fully‐penetrant congenital obstructive hydrocephalus together with brain overgrowth (Zega et al, ). When focusing on common genetic variants, we also found nominally significant association of DUSP16 with schizophrenia.…”

Developmental and social deficits and enhanced sensitivity to prenatal chlorpyrifos in PON1-/- mouse pups and adults

“…On PND 28, the pups were weaned and housed with same sex littermates. Genotype was confirmed by PCR using a tail snip from the dams and sires before breeding as previously described [52].…”