Rethinking the cilia hypothesis of hydrocephalus Duy, Phan Q.; Greenberg, Ana B.W.; Butler, William E. ...
Neurobiology of disease,
December 2022, 2022-12-00, 20221201, 2022-12-01, Letnik:
175
Journal Article
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Dysfunction of motile cilia in ependymal cells has been proposed to be a pathogenic cause of cerebrospinal fluid (CSF) overaccumulation leading to ventricular expansion in hydrocephalus, primarily ...based on observations of enlarged ventricles in mouse models of primary ciliary dyskinesia. Here, we review human and animal evidence that warrants a rethinking of the cilia hypothesis in hydrocephalus. First, we discuss neuroembryology and physiology data that do not support a role for ependymal cilia as the primary propeller of CSF movement across the ventricles in the human brain, particularly during in utero development prior to the functional maturation of ependymal cilia. Second, we highlight that in contrast to mouse models, motile ciliopathies infrequently cause hydrocephalus in humans. Instead, gene mutations affecting motile cilia function impact not only ependymal cilia but also motile cilia found in other organ systems outside of the brain, causing a clinical syndrome of recurrent respiratory infections and situs inversus, symptoms that do not typically accompany most cases of human hydrocephalus. Finally, we postulate that certain cases of hydrocephalus associated with ciliary gene mutations may arise not necessarily just from loss of cilia-generated CSF flow but also from altered neurodevelopment, given the potential functions of ciliary genes in signaling and neural stem cell fate beyond generating fluid flow. Further investigations are needed to clarify the link between motile cilia, CSF physiology, and brain development, the understanding of which has implications for the care of patients with hydrocephalus and other related neurodevelopmental disorders.
Abstract
Hydrocephalus is classically considered to be a disorder of altered cerebrospinal fluid (CSF) circulation, leading to the dilation of cerebral ventricles. Here, we report a clinical case of ...a patient who presented with fetal-onset hydrocephalus with diffusely reduced cortical and white matter volumes resulting from a genetic mutation in L1CAM, a well-known hydrocephalus disease gene involved in neuronal cell adhesion and axon development. After CSF was drained from the ventricle intraoperatively, the patient’s cortical mantle collapsed and exhibited a “floppy” appearance on neuroimaging, suggesting an inability of the hydrocephalic brain to maintain its structural integrity. The case provides clinical support for altered brain biomechanical properties in human hydrocephalus and adds to the emerging hypothesis that altered brain development with secondary impact on brain structural stability may contribute to ventricular enlargement in some subsets of hydrocephalus.
Characterized by enlarged brain ventricles, hydrocephalus is a common neurological disorder classically attributed to a primary defect in cerebrospinal fluid (CSF) homeostasis. Microcephaly ("small ...head") and hydrocephalus are typically viewed as two mutually exclusive phenomenon, since hydrocephalus is thought of as a fluid "plumbing" disorder leading to CSF accumulation, ventricular dilatation, and resultant macrocephaly. However, some cases of hydrocephalus can be associated with microcephaly. Recent work in the genomics of congenital hydrocephalus (CH) and an improved understanding of the tropism of certain viruses such as Zika and cytomegalovirus are beginning to shed light into the paradox "microcephalic hydrocephalus" by defining prenatal neural stem cells (NSC) as the spatiotemporal "scene of the crime." In some forms of CH and viral brain infections, impaired fetal NSC proliferation leads to decreased neurogenesis, cortical hypoplasia and impaired biomechanical interactions at the CSF-brain interface that collectively engender ventriculomegaly despite an overall and often striking decrease in head circumference. The coexistence of microcephaly and hydrocephalus suggests that these two phenotypes may overlap more than previously appreciated. Continued study of both conditions may be unexpectedly fertile ground for providing new insights into human NSC biology and our understanding of neurodevelopmental disorders.
Tripartite motif 71 (Trim71)/lineage defective 41 (lin-41) is the primary target of the ancient lethal 7 (let-7) miRNA that is essential for survival and development across animal phylogeny. Recent ...work identified Trim71 as a critical regulator of mammalian neural stem cell (NSC) fate and a bona fide human disease gene in congenital hydrocephalus (CH). Studying TRIM71 as a paradigm of NSC involvement in CH is a remarkable opportunity to better understand the mechanisms that regulate the timing of brain development and the pathogenesis of the most common pediatric neurosurgical disorder.
Epilepsy is a common neurological disorder characterized by recurrent and unprovoked seizures thought to arise from impaired balance between neuronal excitation and inhibition. Our understanding of ...the neurophysiological mechanisms that render the brain epileptogenic remains incomplete, reflected by the lack of satisfactory treatments that can effectively prevent epileptic seizures without significant drug-related adverse effects. Type 2 K
-Cl
cotransporter (KCC2), encoded by
, is important for chloride homeostasis and neuronal excitability. KCC2 dysfunction attenuates Cl
extrusion and impairs GABAergic inhibition, and can lead to neuronal hyperexcitability. Converging lines of evidence from human genetics have secured the link between KCC2 dysfunction and the development of epilepsy. Here, we review KCC2 mutations in human epilepsy and discuss potential therapeutic strategies based on the functional impact of these mutations. We suggest that a strategy of augmenting KCC2 activity by antagonizing its critical inhibitory phosphorylation sites may be a particularly efficacious method of facilitating Cl
extrusion and restoring GABA inhibition to treat medication-refractory epilepsy and other seizure disorders.
Daily changes in light and food availability are major time cues that influence circadian timing
. However, little is known about the circuits that integrate these time cues to drive a coherent ...circadian output
. Here we investigate whether retinal inputs modulate entrainment to nonphotic cues such as time-restricted feeding. Photic information is relayed to the suprachiasmatic nucleus (SCN)-the central circadian pacemaker-and the intergeniculate leaflet (IGL) through intrinsically photosensitive retinal ganglion cells (ipRGCs)
. We show that adult mice that lack ipRGCs from the early postnatal stages have impaired entrainment to time-restricted feeding, whereas ablation of ipRGCs at later stages had no effect. Innervation of ipRGCs at early postnatal stages influences IGL neurons that express neuropeptide Y (NPY) (hereafter, IGL
neurons), guiding the assembly of a functional IGL
-SCN circuit. Moreover, silencing IGL
neurons in adult mice mimicked the deficits that were induced by ablation of ipRGCs in the early postnatal stages, and acute inhibition of IGL
terminals in the SCN decreased food-anticipatory activity. Thus, innervation of ipRGCs in the early postnatal period tunes the IGL
-SCN circuit to allow entrainment to time-restricted feeding.
Motoneurons establish a critical link between the CNS and muscles. If motoneurons do not develop correctly, they cannot form the required connections, resulting in movement defects or paralysis. ...Compromised development can also lead to degeneration because the motoneuron is not set up to function properly. Little is known, however, regarding the mechanisms that control vertebrate motoneuron development, particularly the later stages of axon branch and dendrite formation. The motoneuron disease spinal muscular atrophy (SMA) is caused by low levels of the survival motor neuron (SMN) protein leading to defects in vertebrate motoneuron development and synapse formation. Here we show using zebrafish as a model system that SMN interacts with the RNA binding protein (RBP) HuD in motoneurons
during formation of axonal branches and dendrites. To determine the function of HuD in motoneurons, we generated zebrafish
mutants and found that they exhibited decreased motor axon branches, dramatically fewer dendrites, and movement defects. These same phenotypes are present in animals expressing low levels of SMN, indicating that both proteins function in motoneuron development. HuD binds and transports mRNAs and one of its target mRNAs,
, is involved in axonal outgrowth. We found that
was decreased in both
and
mutants. Importantly, transgenic expression of HuD in motoneurons of
mutants rescued the motoneuron defects, the movement defects, and
mRNA levels. These data support that the interaction between SMN and HuD is critical for motoneuron development and point to a role for RBPs in SMA.
In zebrafish models of the motoneuron disease spinal muscular atrophy (SMA), motor axons fail to form the normal extent of axonal branches and dendrites leading to decreased motor function. SMA is caused by low levels of the survival motor neuron (SMN) protein. We show in motoneurons
that SMN interacts with the RNA binding protein, HuD. Novel mutants reveal that HuD is also necessary for motor axonal branch and dendrite formation. Data also revealed that both SMN and HuD affect levels of an mRNA involved in axonal growth. Moreover, expressing HuD in SMN-deficient motoneurons can rescue the motoneuron development and motor defects caused by low levels of SMN. These data support that SMN:HuD complexes are essential for normal motoneuron development and indicate that mRNA handling is a critical component of SMA.
Hydrocephalus is the most common neurosurgical disorder worldwide and is characterized by enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles resulting from failed CSF homeostasis. ...Since the 1840s, physicians have observed inflammation in the brain and the CSF spaces in both posthaemorrhagic hydrocephalus (PHH) and postinfectious hydrocephalus (PIH). Reparative inflammation is an important protective response that eliminates foreign organisms, damaged cells and physical irritants; however, inappropriately triggered or sustained inflammation can respectively initiate or propagate disease. Recent data have begun to uncover the molecular mechanisms by which inflammation - driven by Toll-like receptor 4-regulated cytokines, immune cells and signalling pathways - contributes to the pathogenesis of hydrocephalus. We propose that therapeutic approaches that target inflammatory mediators in both PHH and PIH could address the multiple drivers of disease, including choroid plexus CSF hypersecretion, ependymal denudation, and damage and scarring of intraventricular and parenchymal (glia-lymphatic) CSF pathways. Here, we review the evidence for a prominent role of inflammation in the pathogenic mechanism of PHH and PIH and highlight promising targets for therapeutic intervention. Focusing research efforts on inflammation could shift our view of hydrocephalus from that of a lifelong neurosurgical disorder to that of a preventable neuroinflammatory condition.
Abstract
Recent trio-based whole-exome sequencing studies of congenital hydrocephalus and nonsyndromic craniosynostosis have identified multiple novel disease genes that have illuminated the ...pathogenesis of these disorders and shed new insight into the genetic regulation of human brain and skull development. Continued study of these and other historically understudied developmental anomalies has the potential to replace the current antiquated, anatomically based disease classification systems with a molecular nomenclature that may increase precision for genetic counseling, prognostication, and surgical treatment stratification—including when not to operate. Data will also inform future clinical trials, catalyze the development of targeted therapies, and generate infrastructure and publicly available data sets relevant for other related nonsurgical neurodevelopmental and neuropsychiatric diseases.
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