Cellular divisions require mechanisms that duplicate genome and segregate it to form daughter cells. A key structure for chromosome segregation is a chromatin region called centromere.
Centromeres recruit kinetochore complex, a proteinaceous machinery that create attachments to the microtubule of the mitotic spindle. Centromere is a key player in genome integrity and chromosome separation during mitosis hence any alterations of centromere architecture can cause cell cycle defects leading to chromosomal instability hallmark of several human pathologies as cancer and developmental disorders.
The improvement of sequencing methodologies has been allowed to discover genes implicated in genetic rare diseases. Indeed, in the last few years, knowledge about primary microcephaly, a rare neurological condition characterized by a reduced brain size and mental retardation, has greatly increased thanks also to model systems such as Drosophila since that many of the genes involved in human microcephaly are conserved in fruit fly.
In the past few years, it has been identified a novel gene implicated in primary microcephaly; in patients cells it has been discovered a mutation in PHC1 gene, a human orthologue of polyhomeotic in Drosophila.
Polyhomeotic is the member of Polycomb group (Pc-G) proteins that are highly conserved proteins required for the maintenance of a repressed state of target gene transcription.
My preliminary results show that in Drosophila S2 cells polyhomeotic play a key role in chromosome segregation, epigenetic regulation of the centromere and especially in CENP-A loading, a specific marker crucial for centromere specification.
Based on these findings, using Drosophila as a model organism, I plan to perform genetic, molecular and cytological experiments in order to investigate polyhomeotic gene in microcephaly focusing on its centromere function. This study will help to elucidate the molecular mechanisms underlying the pathological condition.
Recent studies show that genes encoding mitotic factors are involved in human neuronal disorders thanks to technological advancements in next-generation sequencing that has enormously increased the discovery of pathologies-related genes.
Furthermore, microcephaly-linked mitotic genes operate in chromosome segregation and cell division regulation in neuronal stem cells.
Despite many studies have been carried out to further elucidate molecular pathways associated with primary microcephaly knowledge is still incomplete.
Thus, I speculate that my studies can provide more information on microcephaly conditions and mitotic genes involved in physiological neuronal development.
In addition, these studies could help to clarify the crucial role of centromere and kinetochore complex not only in neurodevelopmental disorders but also in central nervous system growth and human brain evolution.
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