Pericentrin is a Kinesin-1 Activator that Drives Centriole Motility

Centrosome positioning is essential for their function. Typically, centrosomes are transported to various cellular locations through the interaction of centrosome nucleated microtubules with motor proteins. However, it remains unknown how centrioles migrate in cellular contexts in which centrioles do not nucleate microtubules. Here, we demonstrate that during interphase inactive centrioles move directly along the noncentrosomal microtubule network as cargo for the motor protein Kinesin-1. We identify Pericentrin-Like-Protein (PLP) as a novel Kinesin-1 interacting molecule essential for centriole motility. PLP directly interacts with the cargo binding domain of Kinesin-1 and they comigrate on microtubules in vitro. Finally, we demonstrate that PLP-Kinesin-1 dependent transport is essential for centrosome asymmetry age dependent centrosome inheritance in asymmetric stem cell division.

A simple and direct method to define clonal selection in somatic mosaicism

Dividing somatic stem cells acquire DNA changes marking different clones. With time, clones can become large, either stochastically through neutral drift, or increased fitness and consequent selection. We present a simple, direct, and general approach that distinguishes between these two processes in normal somatic tissue in individuals. The method relies on single time point whole genome sequencing to study somatic mosaicism as tissues age. Using this method, we show that in human clonal hemopoiesis (CH), clones with CH driver mutations, that comprise a median of 24% of hematopoiesis originate decades before they are detected. They expand, through selection by a median of 26% per year. Overall, there is a 3-fold increased rate of stem cell division and an 8.6-fold increase in active long-term stem cells.

Regulation of Neural Stem Cell Competency and Commitment during Indirect Neurogenesis

Indirect neurogenesis, during which neural stem cells generate neurons through intermediate progenitors, drives the evolution of lissencephalic brains to gyrencephalic brains. The mechanisms that specify intermediate progenitor identity and that regulate stem cell competency to generate intermediate progenitors remain poorly understood despite their roles in indirect neurogenesis. Well-characterized lineage hierarchy and available powerful genetic tools for manipulating gene functions make fruit fly neural stem cell (neuroblast) lineages an excellent in vivo paradigm for investigating the mechanisms that regulate neurogenesis. Type II neuroblasts in fly larval brains repeatedly undergo asymmetric divisions to generate intermediate neural progenitors (INPs) that undergo limited proliferation to increase the number of neurons generated per stem cell division. Here, we review key regulatory genes and the mechanisms by which they promote the specification and generation of INPs, safeguarding the indirect generation of neurons during fly larval brain neurogenesis. Homologs of these regulators of INPs have been shown to play important roles in regulating brain development in vertebrates. Insight into the precise regulation of intermediate progenitors will likely improve our understanding of the control of indirect neurogenesis during brain development and brain evolution.

Constrained optimisation of divisional load in hierarchically-organised tissues during homeostasis

It has been hypothesised that the structure of tissues and the hierarchy of differentiation from stem cell to terminally-differentiated cell play a significant role in reducing the incidence of cancer in that tissue. One specific mechanism by which this risk can be reduced is by minimising the number of divisions -- and hence the mutational risk -- that cells accumulate as they divide to maintain tissue homeostasis. Here we investigate a mathematical model of cell division in a hierarchical tissue, calculating and minimising the divisional load while constraining parameters such that homeostasis is maintained. We show that the minimal divisional load is achieved by binary division tress with progenitor cells incapable of self-renewal. Contrary to the protection hypothesis, we find that an increased stem cell turnover can lead to lower divisional load. Furthermore, we find that the optimal tissue structure depends on the time horizon of the duration of homeostasis, with faster stem cell division favoured in short-lived organisms and more progenitor compartments favoured in longer-lived organisms.

Distinct roles of haspin in stem cell division and male gametogenesis

The kinase haspin phosphorylates histone H3 at threonine-3 (H3T3ph) during mitosis. H3T3ph provides a docking site for the Chromosomal Passenger Complex at the centromere, enabling correction of erratic microtubule-chromosome contacts. Although this mechanism is operational in all dividing cells, haspin-null mice do not exhibit developmental anomalies, apart from aberrant testis architecture. Investigating this problem, we show here that mouse embryonic stem cells that lack or overexpress haspin, albeit prone to chromosome misalignment during metaphase, can still divide, expand and differentiate. RNA sequencing reveals that haspin dosage affects severely the expression levels of several genes that are involved in male gametogenesis. Consistent with a role in testis-specific expression, H3T3ph is detected not only in mitotic spermatogonia and meiotic spermatocytes, but also in non-dividing cells, such as haploid spermatids. Similarly to somatic cells, the mark is erased in the end of meiotic divisions, but re-installed during spermatid maturation, subsequent to methylation of histone H3 at lysine-4 (H3K4me3) and arginine-8 (H3R8me2). These serial modifications are particularly enriched in chromatin domains containing histone H3 trimethylated at lysine-27 (H3K27me3), but devoid of histone H3 trimethylated at lysine-9 (H3K9me3). The unique spatio-temporal pattern of histone H3 modifications implicates haspin in the epigenetic control of spermiogenesis.

Episome partitioning and symmetric cell divisions: Quantifying the role of random events in the persistence of HPV infections

Human Papillomaviruses (HPV) are one of the most prevalent sexually transmitted infections (STI) and the most oncogenic viruses known to humans. The vast majority of HPV infections clear in less than 3 years, but the underlying mechanisms, especially the involvement of the immune response, are still poorly known. Building on earlier work stressing the importance of randomness in the type of cell divisions in the clearance of HPV infection, we develop a stochastic mathematical model of HPV dynamics that combines the previous aspect with an explicit description of the intracellular level. We show that the random partitioning of virus episomes upon stem cell division and the occurrence of symmetric divisions dramatically affect viral persistence. These results call for more detailed within-host studies to better understand the relative importance of stochasticity and immunity in HPV infection clearance.