Kaiser M (2017) Trends Cogn Sci "Mechanisms of Connectome Development."

Kaiser M

[Trends Cogn Sci, 2017]

At the centenary of D'Arcy Thompson's seminal work 'On Growth and Form', pioneering the description of principles of morphological changes during development and evolution, recent experimental advances allow us to study change in anatomical brain networks. Here, we outline potential principles for connectome development. We will describe recent results on how spatial and temporal factors shape connectome development in health and disease. Understanding the developmental origins of brain diseases in individuals will be crucial for deciding on personalized treatment options. We argue that longitudinal studies, experimentally derived parameters for connection formation, and biologically realistic computational models are needed to better understand the link between brain network development, network structure, and network function.

Kaiser CM et al. (2012) Biophys J "Tracking UNC-45 chaperone-myosin interaction with a titin mechanical reporter."

Ma L, Oberhauser AF, Kaiser CM, Bujalowski PJ, Epstein HF, Anderson J

[Biophys J, 2012]

Myosins are molecular motors that convert chemical energy into mechanical work. Allosterically coupling ATP-binding, hydrolysis, and binding/dissociation to actin filaments requires precise and coordinated structural changes that are achieved by the structurally complex myosin motor domain. UNC-45, a member of the UNC-45/Cro1/She4p family of proteins, acts as a chaperone for myosin and is essential for proper folding and assembly of myosin into muscle thick filaments in vivo. The molecular mechanisms by which UNC-45 interacts with myosin to promote proper folding of the myosin head domain are not known. We have devised a novel approach, to our knowledge, to analyze the interaction of UNC-45 with the myosin motor domain at the single molecule level using atomic force microscopy. By chemically coupling a titin I27 polyprotein to the motor domain of myosin, we introduced a mechanical reporter. In addition, the polyprotein provided a specific attachment point and an unambiguous mechanical fingerprint, facilitating our atomic force microscopy measurements. This approach enabled us to study UNC-45-motor domain interactions. After mechanical unfolding, the motor domain interfered with refolding of the otherwise robust I27 modules, presumably by recruiting them into a misfolded state. In the presence of UNC-45, I27 folding was restored. Our single molecule approach enables the study of UNC-45 chaperone interactions with myosin and their consequences for motor domain folding and misfolding in mechanistic detail.

Kaiser M et al. (2011) Network "Evolution and development of brain networks: from Caenorhabditis elegans to Homo sapiens."

Varier S, Kaiser M

[Network, 2011]

Neural networks show a progressive increase in complexity during the time course of evolution. From diffuse nerve nets in Cnidaria to modular, hierarchical systems in macaque and humans, there is a gradual shift from simple processes involving a limited amount of tasks and modalities to complex functional and behavioral processing integrating different kinds of information from highly specialized tissue. However, studies in a range of species suggest that fundamental similarities, in spatial and topological features as well as in developmental mechanisms for network formation, are retained across evolution. 'Small-world' topology and highly connected regions (hubs) are prevalent across the evolutionary scale, ensuring efficient processing and resilience to internal (e.g. lesions) and external (e.g. environment) changes. Furthermore, in most species, even the establishment of hubs, long-range connections linking distant components, and a modular organization, relies on similar mechanisms. In conclusion, evolutionary divergence leads to greater complexity while following essential developmental constraints.

Kaiser M et al. (2009) Cereb Cortex "A simple rule for axon outgrowth and synaptic competition generates realistic connection lengths and filling fractions."

van Ooyen A, Hilgetag CC, Kaiser M

[Cereb Cortex, 2009]

Neural connectivity at the cellular and mesoscopic level appears very specific and is presumed to arise from highly specific developmental mechanisms. However, there are general shared features of connectivity in systems as different as the networks formed by individual neurons in Caenorhabditis elegans or in rat visual cortex and the mesoscopic circuitry of cortical areas in the mouse, macaque, and human brain. In all these systems, connection length distributions have very similar shapes, with an initial large peak and a long flat tail representing the admixture of long-distance connections to mostly short-distance connections. Furthermore, not all potentially possible synapses are formed, and only a fraction of axons (called filling fraction) establish synapses with spatially neighboring neurons. We explored what aspects of these connectivity patterns can be explained simply by random axonal outgrowth. We found that random axonal growth away from the soma can already reproduce the known distance distribution of connections. We also observed that experimentally observed filling fractions can be generated by competition for available space at the target neurons--a model markedly different from previous explanations. These findings may serve as a baseline model for the development of connectivity that can be further refined by more specific mechanisms.

Das L et al. (2018) Genomics "An integrated approach for identification of exon locations using recursive Gauss Newton tuned adaptive Kaiser window."

Nanda S, Das JK, Das L

[Genomics, 2018]

Identification of exon location in a DNA sequence has been considered as the most demanding and challenging research topic in the field of Bioinformatics. This work proposes a robust approach combining the Trigonometric mapping with Adaptive tuned Kaiser Windowing approach for locating the protein coding regions (EXONS) in a genetic sequence. For better convergence as well as improved accurateness, the side lobe height control parameter () of Kaiser Window in the proposed algorithm is made adaptive to track the changing dynamics of the genetic sequence. This yields better tracking potential of the anticipated Adaptive Kaiser algorithm as it uses the recursive Gauss Newton tuning which in turn utilizes the covariance of the error signal to tune the factor which has been shown through numerous simulation results under a variety of practical test conditions. A detailed comparative analysis with the existing mapping schemes, windowing techniques, and other signal processing methods like SVD, AN, DFT, STDFT, WT, and ST has also been included in the paper to focus on the strength and efficiency of the proposed approach. Moreover, some critical performance parameters have been computed using the proposed approach to investigate the effectiveness and robustness of the algorithm. In addition to this, the proposed approach has also been successfully applied on a number of benchmark gene sets like Musmusculus, Homosapiens, and C. elegans, etc., where the proposed approach revealed efficient prediction of exon location in contrast to the other existing mapping methods.

Kaiser M et al. (2006) PLoS Comput Biol "Nonoptimal component placement, but short processing paths, due to long-distance projections in neural systems."

Hilgetag CC, Kaiser M

[PLoS Comput Biol, 2006]

It has been suggested that neural systems across several scales of organization show optimal component placement, in which any spatial rearrangement of the components would lead to an increase of total wiring. Using extensive connectivity datasets for diverse neural networks combined with spatial coordinates for network nodes, we applied an optimization algorithm to the network layouts, in order to search for wire-saving component rearrangements. We found that optimized component rearrangements could substantially reduce total wiring length in all tested neural networks. Specifically, total wiring among 95 primate (Macaque) cortical areas could be decreased by 32%, and wiring of neuronal networks in the nematode Caenorhabditis elegans could be reduced by 48% on the global level, and by 49% for neurons within frontal ganglia. Wiring length reductions were possible due to the existence of long-distance projections in neural networks. We explored the role of these projections by comparing the original networks with minimally rewired networks of the same size, which possessed only the shortest possible connections. In the minimally rewired networks, the number of processing steps along the shortest paths between components was significantly increased compared to the original networks. Additional benchmark comparisons also indicated that neural networks are more similar to network layouts that minimize the length of processing paths, rather than wiring length. These findings suggest that neural systems are not exclusively optimized for minimal global wiring, but for a variety of factors including the minimization of processing steps.

Hodgkin J (2004) Curr Biol "Jonathan Hodgkin."

Hodgkin J

[Curr Biol, 2004]

Jonathan Hodgkin graduated from Oxford in 1971 and then did a PhD with Sydney Brenner at MRC LMB in Cambridge, studying behavioural genetics in the nematode Caenorhabditis elegans. Later, after a couple of years working with myxobacteria as a postdoc in Dale Kaiser''s lab at Stanford, he returned to LMB as a staff member, where he remained for most of the subsequent two decades. In the year 2000, he moved to Oxford as Professor of Genetics in the Department of Biochemistry, switching his major research interests from developmental genetics and sex determination to the study of host-pathogen interactions in the worm. For the past ten years, he has acted as curator of the C. elegans genetic map and gene nomenclature, and he is currently President of the Genetics Society of Great Britain.

Reinhardt F et al. (2024) Heliyon "Evolution of neuropeptide Y/RFamide-like receptors in nematodes."

Reinhardt F, Stadler PF, Kaiser A, Proemel S

[Heliyon, 2024]

The Neuropeptide Y/RFamide-like receptors belong to the Rhodopsin-like G protein-coupled receptors G protein-coupled receptors (GPCRs) and are involved in functions such as locomotion, feeding and reproduction. With 41 described receptors they form the best-studied group of neuropeptide GPCRs in <i>Caenorhabditis elegans</i>. In order to understand the expansion of the Neuropeptide Y/RFamide-like receptor family in nematodes, we started from the sequences of selected receptor paralogs in <i>C. elegans</i> as query and surveyed the corresponding orthologous sequences in another 159 representative nematode target genomes. To this end we employed a automated pipeline based on ExonMatchSolver, a tool that solves the paralog-to-contig assignment problem. Utilizing subclass-specific HMMs we were able to detect a total of 1557 Neuropeptide Y/RFamide-like receptor sequences (1100 NPRs, 375 FRPRs and 82 C09F12.3) in the 159 target nematode genomes investigated here. These sequences demonstrate a good conservation of the Neuropeptide Y/RFamide-like receptors across the Nematoda and highlight the diversification of the family in nematode evolution. No other genus shares all Neuropeptide Y/RFamide-like receptors with the genus <i>Caenorhabditis</i>. At the same time, we observe large numbers of clade specific duplications and losses of family members across the phylum Nematoda.

Gross, V. et al. (2019) International Worm Meeting "The neuropeptide Y GPCR system is pharmacologically and functionally conserved in the model organism C. elegans."

Schoneberg, T., Kaiser, A., Gross, V., Promel, S., Gershkovich, M.

[International Worm Meeting, 2019]

The neuropeptide Y (NPY) family is a well-studied system due to the essential roles in regulating food consumption, control of mood and anxiety or ethanol intake. Several neuropeptides activate different G protein-coupled receptors (GPCRs), thus forming a multireceptor/ multiligand system, making neuropeptidergic signaling highly complex. Being a key regulator of essential processes, it is not surprising that neuropeptide signaling is conserved down to basal animals such as protostomes and thus, forms an ancient system. Surprisingly, in Caenorhabditis elegans, there is controversy on the existence of an NPY orthologous system. Upon the discovery of the FMRFamide-like peptide (FLP)/ NPY/ RFamide-like receptor (NPR) system in the nematode, orthology to the human system was suggested. However, later global phylogenetic studies indicated that FLP/ NPR is not truly homologous to the NPY system, but nematode-specific. To gain insights in the pharmacological and functional similarities of the NPR/ FLP and the human NPY system, we conducted a comprehensive comparative pharmacological study of the FLP/ NPR system proving that G protein-coupling and ligand-binding modes are similar to the human NPY system. Further, in vitro and in vivo analyses show cross-reactivity of the NPY with the FLP/ NPR system culminating in the ability of the human GPCRs to functionally substitute FLP/ NPR signaling in C. elegans in vivo. This functional homology of both neuropeptide systems was subsequently utilized to identify FLP-14 as a main driver for chemotaxis. Taken together, our data reveal high levels of pharmacological and functional similarity of human and C. elegans NPY systems, suggesting a homologous relationship, and highlight the importance for physiological as well as molecular studies. Ultimately, our study will contribute to the understanding on how specific neuropeptide receptor signals are translated into physiological function.

Gershkovich MM et al. (2019) Cell Commun Signal "Pharmacological and functional similarities of the human neuropeptide Y system in C. elegans challenges phylogenetic views on the FLP/NPR system."

Kaiser A, GroB VE, Promel S, Gershkovich MM

[Cell Commun Signal, 2019]

BACKGROUND: The neuropeptide Y system affects various processes, among others food intake, and is frequently discussed in the context of targeting obesity. Studies in model organisms are indispensable to enable molecular studies in a physiological context. Although the NPY system is evolutionarily conserved in all bilaterians, in the widely used model Caenorhabditis elegans there is controversy on the existence of NPY orthologous molecules. While the FMRFamide-like peptide (FLP)/Neuropeptide receptor-Resemblance (NPR) system in the nematode was initially suggested to be orthologous to the mammalian NPY system, later global phylogenetic studies indicate that FLP/NPR is protostome-specific. METHODS: We performed a comprehensive pharmacological study of the FLP/NPR system in transfected cells in vitro, and tested for functional substitution in C. elegans knockout strains. Further, we phenotypically compared different flp loss-of-function strains. Differences between groups were compared by ANOVA and post-hoc testing (Dunnett, Bonferroni). RESULTS: Our pharmacological analysis of the FLP/NPR system including formerly functionally uncharacterized NPY-like peptides from C. elegans demonstrates that G protein-coupling and ligand requirements for receptor activation are similar to the human NPY system. In vitro and in vivo analyses show cross-reactivity of NPY with the FLP/NPR system manifesting in the ability of the human GPCRs to functionally substitute FLP/NPR signaling in vivo. The high pharmacological/functional similarities enabled us to identify C. elegans FLP-14 as a key molecule in avoidance behavior. CONCLUSIONS: Our data demonstrate the pharmacological and functional similarities of human NPY and C. elegans NPR systems. This adds a novel perspective to current phylogenetic reconstructions of the neuropeptide Y system. NPY and NPR receptors are pharmacologically so similar that the human receptors can functionally compensate for the C. elegans ones, suggesting orthologous relationships. This is also underlined by the presence of NPY-like peptides and parallels in peptide requirements for receptor activation. Further, the results presented here highlight the potential of this knowledge for physiological as well as molecular studies on neuropeptide GPCRs such as the NPY system in the future.