Assessing evolutionary and developmental transcriptome dynamics in homologous cell types.

BACKGROUND: During development, complex organ patterns emerge through the precise temporal and spatial specification of different cell types. On an evolutionary timescale, these patterns can change, resulting in morphological diversification. It is generally believed that homologous anatomical structures are built-largely-by homologous cell types. However, whether a common evolutionary origin of such cell types is always reflected in the conservation of their intrinsic transcriptional specification programs is less clear. RESULTS: Here, we developed a user-friendly bioinformatics workflow to detect gene co-expression modules and test for their conservation across developmental stages and species boundaries. Using a paradigm of morphological diversification, the tetrapod limb, and single-cell RNA-sequencing data from two distantly related species, chicken and mouse, we assessed the transcriptional dynamics of homologous cell types during embryonic patterning. With mouse limb data as reference, we identified 19 gene co-expression modules with varying tissue or cell type-restricted activities. Testing for co-expression conservation revealed modules with high evolutionary turnover, while others seemed maintained-to different degrees, in module make-up, density or connectivity-over developmental and evolutionary timescales. CONCLUSIONS: We present an approach to identify evolutionary and developmental dynamics in gene co-expression modules during patterning-relevant stages of homologous cell type specification using single-cell RNA-sequencing data.

Evolutionary analyses of caspase-8 and its paralogs: Deep origins of the apoptotic signaling pathways.

Although Caenorhabditis and Drosophila proved invaluable in unraveling the molecular mechanisms of apoptosis, it is now clear that these animals are of limited value for understanding the evolution of apoptotic systems. Whereas data from these invertebrates led to the assumption that the extrinsic apoptotic pathway is restricted to vertebrates, recent data from cnidarians and sponges indicate that this pathway predates bilaterian origins. Here we review the phylogenetic distribution of caspase-8, the initiator caspase of the extrinsic apoptotic pathway, its paralogs and other components of the network. The ancestral caspase-8 gave rise to four paralogs early in vertebrate evolution, and these have been maintained in many tetrapods. However, eutherians have lost caspase-18 and myomorph rodents have lost caspase-10, these losses suggesting functional redundancy amongst caspase-8 paralogs. The apoptotic network of the eumetazoan ancestor appears to have been complex and vertebrate like, and is only now being revealed by studying simple animals.

Making Ramón y Cajal proud: Development of cell identity and diversity in the cerebral cortex.

Since the beautiful images of Santiago Ramón y Cajal provided a first glimpse into the immense diversity and complexity of cell types found in the cerebral cortex, neuroscience has been challenged and inspired to understand how these diverse cells are generated and how they interact with each other to orchestrate the development of this remarkable tissue. Some fundamental questions drive the field's quest to understand cortical development: what are the mechanistic principles that govern the emergence of neuronal diversity? How do extrinsic and intrinsic signals integrate with physical forces and activity to shape cell identity? How do the diverse populations of neurons and glia influence each other during development to guarantee proper integration and function? The advent of powerful new technologies to profile and perturb cortical development at unprecedented resolution and across a variety of modalities has offered a new opportunity to integrate past knowledge with brand new data. Here, we review some of this progress using cortical excitatory projection neurons as a system to draw out general principles of cell diversification and the role of cell-cell interactions during cortical development.

Influencers in the Somatosensory System: Extrinsic Control of Sensory Neuron Phenotypes.

Somatosensory neurons in dorsal root ganglia (DRG) comprise several main subclasses: high threshold nociceptors/thermoceptors, high- and low-threshold mechanoreceptors, and proprioceptors. Recent years have seen an explosion in the identification of molecules that underlie the functional diversity of these sensory modalities. They also have begun to reveal the developmental mechanisms that channel the emergence of this subtype diversity, solidifying the importance of peripheral instructive signals. Somatic sensory neurons collectively serve numerous essential physiological and protective roles, and as such, an increased understanding of the processes that underlie the specialization of these sensory subtypes is not only biologically interesting but also clinically relevant.

Altered paracrine signaling from the injured knee joint impairs postnatal long bone growth.

Regulation of organ growth is a poorly understood process. In the long bones, the growth plates (GPs) drive elongation by generating a scaffold progressively replaced by bone. Although studies have focused on intrinsic GP regulation, classic and recent experiments suggest that local signals also modulate GP function. We devised a genetic mouse model to study extrinsic long bone growth modulation, in which injury is specifically induced in the left hindlimb, such that the right hindlimb serves as an internal control. Remarkably, when only mesenchyme cells surrounding postnatal GPs were killed, left bone growth was nevertheless reduced. GP signaling was impaired by altered paracrine signals from the knee joint, including activation of the injury response and, in neonates, dampened IGF1 production. Importantly, only the combined prevention of both responses rescued neonatal growth. Thus, we identified signals from the knee joint that modulate bone growth and could underlie establishment of body proportions.