Biology subjects

Newton, A. H.

Publications and source records attributed to Newton, A. H..

5 recordsLinked to original sources

bioRxiv2025

Getting a head start: Craniofacial heterochrony in marsupials involves dynamic changes to molecular and cellular mechanisms underlying neural crest development

The neural crest is a vertebrate innovation central to craniofacial development and evolution. While the gene regulatory networks guiding neural crest development are well characterized, the mechanisms generating species-specific craniofacial diversity remain poorly understood. Marsupials provide a unique model for studying neural crest plasticity, having evolved accelerated patterns of craniofacial development during embryogenesis. This adaptation arises in response to marsupials being born altricial after a short gestation yet require well-developed mouthparts to attach to a teat and continue development in the pouch. However, how marsupials achieve this heterochronic shift in neural crest development is largely unknown. In this study, we investigate the cellular and molecular mechanisms underlying their distinct heterochrony, revealing that marsupials produce dense pre-migratory aggregates of neural crest cells which undergo collective migration as epithelial-like sheets, potentially facilitating rapid establishment of the facial prominences. These cellular behaviours are unique amongst amniotes but resemble patterns in anamniotes which similarly exhibit accelerated craniofacial development to support early feeding. Marsupials appear to have evolved a similar mechanism of neural crest migration to facilitate their developmental heterochrony. These findings suggest that vertebrate neural crest migration may be shaped by the pace of craniofacial development during embryogenesis rather than phylogeny, providing new perspectives on neural crest plasticity and the developmental mechanisms driving craniofacial diversity across vertebrates.

developmental biology↗

bioRxiv2024

Marsupial limb patterning redefines the necessity of lateral plate mesoderm subdivision for limb formation

The tetrapod limb has long served as a model for elucidating molecular and cellular mechanisms driving tissue patterning, development and evolution. While significant advances have been made in understanding the drivers of limb initiation, outgrowth, and patterning, the early morphogenetic processes that transform the lateral plate mesoderm (LPM) into limb fields remain less resolved. Marsupial mammals provide a unique opportunity to investigate these foundational processes due to their accelerated forelimb development, driven by the functional demands of altricial neonates to crawl into the pouch at birth. Heterochronic formation of the forelimbs occurs prior to development of other surrounding structures, offering unparalleled insights into the plasticity of limb field specification. Here, we reveal that marsupial limb initiation and outgrowth bypasses physical subdivision of the LPM, a process previously considered critical for tetrapod limb formation. Instead, limb development proceeds through early activation of LPM-associated genes and proliferation before coelom formation, demonstrating remarkable morphogenetic plasticity. This evolutionary adaptation enables heterochronic limb development, redefining conserved processes to meet extreme functional constraints. These findings challenge previous models of tetrapod limb specification, highlighting the evolutionary plasticity of limb patterning mechanisms and reshaping our understanding of how selective pressures influence foundational developmental events.

developmental biology↗

bioRxiv2023

Heterogeneity in quiescent Müller glia in the uninjured zebrafish retina drive differential responses following photoreceptor ablation

Loss of neurons in the neural retina is a leading cause of vision loss. While humans do not possess the capacity for retinal regeneration, zebrafish can achieve this through activation of resident Muller glia. Remarkably, despite the presence of Muller glia in humans and other mammalian vertebrates, these cells lack an intrinsic ability to contribute to regeneration. Upon activation, zebrafish Muller glia can adopt a stem cell-like state, undergo proliferation and generate new neurons. However, the underlying molecular mechanisms of this activation subsequent retinal regeneration remains unclear. To address this, we performed single-cell RNA sequencing (scRNA-seq) and report remarkable heterogeneity in gene expression within quiescent Muller glia across distinct dorsal, central and ventral retina pools of such cells. Next, we utilised a genetically driven, chemically inducible nitroreductase approach to study Muller glia activation following selective ablation of three distinct photoreceptor subtypes: long wavelength sensitive cones, short wavelength sensitive cones, and rods. There, our data revealed that a region-specific bias in activation of Muller glia exists in the zebrafish retina, and this is independent of the distribution of the ablated cell type across retinal regions. Notably, gene ontology analysis revealed that injury-responsive dorsal and central Muller glia express genes related to dorsal/ventral pattern formation, growth factor activity, and regulation of developmental process. Through scRNA-seq analysis, we identify a shared genetic program underlying initial Muller glia activation and cell cycle entry, followed by differences that drive the fate of regenerating neurons. We observed an initial expression of AP-1 and injury-responsive transcription factors, followed by genes involved in Notch signalling, ribosome biogenesis and gliogenesis, and finally expression of cell cycle, chromatin remodeling and microtubule-associated genes. Taken together, our findings document the regional specificity of gene expression within quiescent Muller glia and demonstrate unique Muller glia activation and regeneration features following neural ablation. These findings will improve our understanding of the molecular pathways relevant to neural regeneration in the retina.

neuroscience↗

bioRxiv2022

Reduced specification of lateral plate mesoderm progenitors underpins heterochronic development of the emu wing

The tetrapod limb has evolved a broad diversity of form and function, enabling vertebrates to adapt to a wide range of environments. One of the most striking examples of this is the evolution of powered flight in birds. However, during the avian radiation, flightless ratites (Paleognathae) secondarily evolved multiple instances of wing reductions, utilizing distinct molecular mechanisms, and displaying heterochrony with flighted birds (Neoaves). Among ratites, the emu displays the most marked reduction of wing anatomy, developing a small wing with a single clawed digit. This major divergence from the typical avian pattern provides a robust model to determine the mechanisms underpinning developmental plasticity in the tetrapod limb. To interrogate the ontogenetic origins of vestigial wing development, we applied comparative single cell transcriptomics of the embryonic emu forelimb field with the chicken, as it possess a typical wing. Stunted wing development in the emu occurs through a heterotopic reduction of lateral plate mesoderm (LPM)-derived limb progenitor cells, and accompanying downregulation of genes associated with LPM development and early limb initiation. Here, forelimb bud initiation and outgrowth is altered by changes to the specification and allocation of limb progenitor cells, acting as an underlying template for pre- and post-patterning mechanisms. These findings provide novel insights into the evolution of limb development in tetrapods, and emphasizes an important, yet underappreciated role for heterotopy as major driver of limb disparity. Significance statementAnimals exhibit a striking variety of morphologies, yet our understanding of how these forms evolve and arise during development are lagging. The emu is a large, flightless bird which has evolved a vestigial wing. This model allows detailed interrogations into the mechanisms which underlie evolution and development of a distinct morphological structure. Through application of comparative single cell transcriptomics between the emu and chicken, we identify an early embryological mechanism, heterotopy, underlying the evolution and vestigial development of the emu wing. This mechanism features reduced allocation of limb bud progenitor cells in the lateral plate mesoderm (LPM). This data provides new information on the mechanisms that underpin evolutionary diversity in morphological features.

evolutionary biology↗

bioRxiv2022

Cell lineage specification during development of the anterior lateral plate mesoderm and forelimb field

The lateral plate mesoderm (LPM) is a transient embryonic tissue that gives rise to a diverse range of mature cell types, including the cardiovascular system, the urogenital system, endoskeleton of the limbs, and mesenchyme of the gut. While the genetic processes that drive development of these tissues are well defined, the early cell fate choices underlying LPM development and specification are poorly understood. In this study, we utilize single-cell transcriptomics to define cell lineage specification during development of the anterior LPM and the forelimb field in the chicken embryo. We identify the molecular pathways directing differentiation of the aLPM towards a somatic or splanchnic cell fate, and subsequent emergence of the forelimb mesenchyme. We establish the first transcriptional atlas of progenitor, transitional and mature cell types throughout the early forelimb field and uncover the global signalling pathways which are active during LPM differentiation and forelimb initiation. Specification of the somatic and splanchnic LPM from undifferentiated mesoderm utilizes distinct signalling pathways and involves shared repression of early mesodermal markers, followed by activation of lineage-specific gene modules. We identify rapid activation of the transcription factor TWIST1 in the somatic LPM preceding activation of known limb initiation genes, such as TBX5, which plays a likely role in epithelial-to-mesenchyme transition of the limb bud mesenchyme. Furthermore, development of the somatic LPM and limb is dependent on ectodermal BMP signalling, where BMP antagonism reduces expression of key somatic LPM and limb genes to inhibit formation of the limb bud mesenchyme. Together, these findings provide new insights into molecular mechanisms that drive fate cell choices during specification of the aLPM and forelimb initiation.

developmental biology↗