In Development this week (Vol. 143, Issue 9)

Here are the highlights from the current issue of Development:

Making inroads into spermatogonial differentiation

Differentiation of spermatogonial cells is a crucial part of spermatogenesis. Many of the key signalling pathways and molecules that are involved in spermatogonial differentiation have been identified, but their precise function at the cellular level as well as their downstream targets are not well understood. In this issue (p. 1502), Ming-Han Tong and colleagues address this with an in-depth look at the role of retinoic acid (RA) in spermatogonial differentiation. The authors specifically block retinoid signalling by introducing a dominant-negative mutant of RA receptor alpha (RARα) targeted to the spermatogonia of the transgenic mice. With this model, they show how a lack of RA signalling completely blocks spermatogonial differentiation in homozygous mice, which is due to the arrest of the undifferentiated cells in the G1/S phase. The authors then use RNA-Seq to probe for possible downstream targets of RA signalling in this context, and identify a role for replication-dependent core histone genes in promoting spermatogonia differentiation. These data make a significant contribution to our understanding of the mechanisms underlying spermatogonial differentiation, and the creation of a novel mouse mutant will be a valuable tool for the field.

Surprising role for CP110 in cilia biogenesis

Primary cilia are antenna-like cellular organelles that act as sensory receptors and also play an important role in signal transduction. Formation of these structures occurs as cells exit the cell cycle, whereupon centrioles migrate to the apical domain and become the basal bodies that anchor the new cilia as it forms. Centrosomal protein CP110 is a crucial regulator of centriolar division during the cell cycle and is thought to act as a key suppressor of ciliogenesis, based on in vitro studies. In this issue (p.1491), Anand Swaroop and colleagues add a new twist to this theory and show that, in vivo, the absence of CP110 results in a failure to make cilia in a Cp110^−/− mouse model. The authors show that ablation ofCp110 causes lethality shortly after birth due to organogenesis defects that are similar to those observed in ciliopathies. Using serum-starved embryonic fibroblasts derived from Cp110^−/− mice, they further demonstrate a failure of basal body docking to membranes during cilia formation. These data challenge the prevailing view and demonstrate a more complex role of CP110 in the ciliogenic pathway, and highlight the importance of in vivo studies for our understanding of ciliogenesis in a physiologically relevant setting.

New model for organ growth termination

Robust growth termination is essential to ensure that organs reach their correct size and grow no further. The precise mechanism of growth termination and the relative contributions of reduced cell proliferation and increased cell differentiation are elusive, and it is not known to what extent these mechanisms may be conserved in different evolutionary contexts. In this issue (p. 1482), Dagmar Iber, Fernando Casares and colleagues combine quantitative three-dimensional measurements with mathematical modelling to investigate growth dynamics in the Drosophila eye disc. The authors show that, much as in other organs and species, the growth rate declines continuously in the eye disc. Moreover, they computationally evaluate how well different candidate growth laws fit with the observed kinetics of organ growth and differentiation, and find that both an exponential and an area-dependent decline in the growth rate fit the data, although the latter offers the most parsimonious explanation. By testing this model prediction in a Drosophila strain with smaller eyes, they confirm experimentally that the area growth rate declines inversely proportional to the total eye disc area, even when the growth rates and relative areas are very different. The area-dependent growth mechanism proposed by the authors is an alternative model to explain the still unresolved issue of how organs know when to stop, and to stop consistently.

Improved protocol for purification of differentiated hepatocytes

Directed differentiation of pluripotent stem cells (PSCs) into hepatocyte-like cells (HLCs) shows great promise for disease modelling as well as regenerative medicine. Unfortunately, current differentiation protocols result in heterogeneity in differentiation efficiency as well as the production of immature and undesirable cell types. In this issue (p. 1475), Chad Cowan and colleagues report an in-depth transcriptional and functional analysis of mature HLCs purified using the membrane marker asialoglycoprotein receptor 1 (ASGR1) from amidst the heterogeneous population of differentiating cells. The authors perform microarray profiling as well as functional assays for albumin and urea secretion and cytochrome activity, and find that the ASGR1⁺ cells exhibit a gene profile and functional characteristics similar to primary human hepatocytes, as compared with the HLCs negative for ASGR1. Although the cells isolated by this method are not perfect mimics of primary adult hepatocytes, the observed increase in homogeneity represents a substantial improvement in the differentiation of HLCs. This approach might therefore serve as a means to overcome the variation in the efficiency of HLC differentiation when starting from different PSC lines.

PLUS…

Heartbreak hotel: a convergence in cardiac regeneration

In February 2016, The Company of Biologists hosted an intimate gathering of leading international researchers at the forefront of experimental cardiovascular regeneration, with its emphasis on ‘Transdifferentiation and Tissue Plasticity in Cardiovascular Rejuvenation’. As discussed by Michael Schneider, participants at the workshop revealed how understanding cardiac growth and lineage decisions at their most fundamental level has transformed the strategies in hand that presently energize the prospects for human heart repair. See the Meeting Review on p. 1435

Plant regeneration: cellular origins and molecular mechanisms

Compared with animals, plants generally possess a high degree of developmental plasticity and display various types of tissue or organ regeneration. Here, Keiko Sugimoto and colleagues summarise how plants control these various types of regeneration and how developmental and environmental constraints can influence plant regenerative regulatory mechanisms. See the Review on p. 1442

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