The development of the central nervous system requires careful processes of cell division and differentiation. An alteration of these events can severely reduce the number of neurons and impair brain function, causing severe symptoms such as intellectual disability, movement disorders and epilepsy.
Our group studies how the proliferation, vitality and differentiation of neurons can be altered by different genetic mutations, resulting in brain size (microcephaly) and in other neurodevelopmental disorders. Furthermore, we seek to understand how the molecular mechanisms of microcephaly can provide useful therapeutic targets to fight brain tumors, in particular those affecting the pediatric age, such as medulloblastoma.
The human brain is composed of approximately 90 billion neurons, which are generated during embryonic life starting from many different types of neural stem cells, whose proliferation is extremely well organized in space and time. Indeed, stem cells’ proliferation is very intense during early brain development, but chases almost completely in post-natal life. If too few neurons are produced or too many neurons die during development, the brain volume can be very compromised, a condition commonly known as microcephaly. Although a significantly reduced brain volume can be compatible with normal brain function and intelligence, microcephaly is frequently associated with strongly invalidating symptoms, such as intellectual disability, epilepsy and cerebral palsy. Microcephaly can be the result of rare genetic disorders, mostly characterized by autosomal recessive inheritance. Even more frequently, it is produced by environmental factors, such as hypoxia, drugs and alcohol exposure or infectious agents, such as Rubella, Toxoplasmosis, Cytomegalovirus or Zyka virus. Research conducted in the last decade has shown that all these conditions may affect common molecular pathways, regulating genome stability, cell proliferation, cell survival and determination of cell identity.
The main focus of our group is to understand how these common mechanisms are related and to develop new strategies that may prevent neuron loss during development, thereby attenuating the consequences of microcephaly-causing insults. We are also studying how abnormal development may lead to abnormal neural circuits, not only in genetic microcephaly, but also in other neurodevelopmental disorders for which a genetic mutation has been found or suspected.
Implementation of models for the study of neurodegenerative diseases and neurodevelopment
Despite the constant increase of the frequency of neurological disorders of genetic origin, not many solutions for reliable preclinical diagnosis and development of effective treatments have been identified. One of the most limiting factors for these activities is the scarceness of suitable experimental models, capable of connecting clinical and biological studies. This problem has become particularly evident after the strong advance of the possibility to genetically study patients, offered by modern sequencing technologies. With the aim of increasing the integration of NICO with clinical research centers, we have implemented in our institute high-throughput models for the functional study of mutations: in vitro, through immortalized cell lines and brain organoids; in vivo, using not only transgenic mice but also the genetically treatable model Caenorhabditis elegans.
Specifically, our research aims to:
Clarify how mutations in Citron kinase lead to microcephaly
Citron kinase (CITK) is a protein that regulates the very last step of the cell division cycle, commonly known as cytokinesis, responsible for splitting a dividing cell into the two daughters. We have first discovered that the complete loss of this protein leads to a severe form of microcephaly in experimental models. Recently, genome sequencing of patients affected by severe microcephaly has identified mutations in the Citron kinase gene, demonstrating its role in pathogenesis of human microcephaly. We know that the neural progenitors of individuals carrying CITK mutations fail to divide and undergo genomic instability and programmed cell death, leading to strong reduction of the neuron number. We are working to clarify how cytokinesis failure and DNA damage may lead to cell death, and whether other mechanisms may be responsible for inducing apoptosis or reducing neuron numbers.
Dissecting the molecular consequences of CITK loss
CITK was originally identified as a protein important for remodeling the actin cytoskeleton. We have recently found that it is even more important to regulate the stability of microtubules, and that this function is crucial for completing cytokinesis, for spindle orientation as well as to prevent the accumulation of DNA double strand breaks
Modeling genetic disorders in C. elegans to study disease mechanisms and to identify possible therapies
The nematode Caenorhabditis elegans is an extremely powerful and versatile experimental model, which allows to study in great detail the molecular mechanisms of human diseases. Indeed, despite hundreds of million years of evolution from a common ancestor, humans and nematodes still possess a high percentage of common genes, encoding even more conserved proteins. For this reason, many human mutations can be studied in C. elegans, allowing to identify with great speed the cellular and molecular mechanisms responsible for disease pathogenesis. Nematode genes can be modulated and mutated very easily and the consequences of these modifications on nervous system organization, morphology and physiology, as well as on the behavior, can be studied at low cost and in a very high number of individuals. By studying how C. elegans nervous system responds to mutations and other stressors we can reveal the fundamental principles of neural plasticity and resilience. The underlying mechanisms can, in turn, be used to combat neurodevelopmental and neurodegenerative diseases and to formulate strategies for enhancing resilience to environmental stimuli, including the presence of chemical pollutants as well as stressing physical conditions, such as those that characterize spaceflight.
CITK as a possible target for cancer therapy
We are addressing the possibility that the function of CITK may be essential for proliferation in medulloblastomas, devastating brain tumors of the infancy that urgently require the development of new therapies.
