Biology subjects

Schwarz, Q.

Publications and source records attributed to Schwarz, Q..

7 recordsLinked to original sources

bioRxiv2025

Neural crest cell derived DKK1 modulates Wnt signalling in the second heart field to orchestrate cardiac outflow tract development

Heart morphogenesis is highly complex, and depends on the generation of diverse cell types which interact with each other in an orchestrated manner to remodel the primitive heart tube into a functional organ. Cardiac outflow tract formation critically depends on continued contribution of cardiac progenitor cells from the anterior second heart field to ensure proper growth of the outflow tract. Prior to entering the outflow tract, neural crest cells migrate in close apposition to the second heart field and may play important roles in regulating second heart field growth dynamics, however the molecular mechanisms by which neural crest cells interact with the second heart field have remained elusive. Here, we discover that neural crest cells are a primary source of Dickkopf1 (DKK1), a secreted Wnt signalling inhibitor, which modulates Wnt signalling activity in the second heart field to impose a balance between progenitor maintenance and differentiation. Further, we identify the ubiquitin ligase NEDD4 as a critical regulator of DKK1 levels, with disruption of Nedd4 activity leading to outflow tract defects. In the context of disease pathogenicity, we show a novel human congenital heart disease variant of NEDD4 has lost the ability to ubiquitinate DKK1, and is associated with heart defects in a mouse model of the genetic variant. Our findings point to an unexpected role for neural crest cells acting as a rheostat of Wnt signalling activity in cardiac progenitors, identifying a new molecular pathway underpinning correct outflow tract morphogenesis, and a new causative factor of congenital heart disease.

developmental biology↗

bioRxiv2025

NEDD4 promotes Sertoli cell proliferation and adult Leydig cell differentiation in the murine testis

Successful testis development relies on the coordinated differentiation and assembly of various cell types to establish both endocrine and reproductive functions. The ubiquitin ligase NEDD4 has emerged as a key player in murine testis development, with this enzyme being implicated in gonadal sex determination and spermatogonial stem cell differentiation. Here, we report hitherto uncharacterized roles of NEDD4 in postnatal testis development. Utilizing Nr5a1- and Amh-Cre drivers to conditionally ablate Nedd4 in testicular somatic cells, we show that NEDD4 promotes Sertoli cell proliferation through the modulation of the PI3K-AKT signaling pathway. This ubiquitin ligase also ensures proper differentiation of adult Leydig cells and may contribute to murine steroidogenesis. Furthermore, NEDD4 is essential for adrenal gland differentiation, as its loss results in adrenal dysgenesis. These findings highlight NEDD4 as a crucial factor in testis development, emphasizing the importance of ubiquitination and post-translational modifications in reproductive biology.

developmental biology↗

bioRxiv2023

Motor nerves direct the development of the sympathetic nervous system

The sympathetic nervous system controls a wide spectrum of bodily functions including operation of vessels, cardiac rhythm, and the "flight or fight response". Sympathetic neurons, which are neural crest-derived, develop in coordination with presynaptic motor nerves extending from the central nervous system (CNS). By using nerve-selective genetic ablations, we revealed that sympathetic ganglia development depends on CNS-derived motor innervation. In the absence of preganglionic motor nerves, trunk sympathetic chain ganglia were fragmented and smaller in size, while cervical ganglia were severely misshapen. Sympathetic neurons were misplaced along sensory fibers and projected towards abnormal paths, in some cases invading the sensory dorsal root ganglia. The misplaced progenitors of sympathoblasts corresponded to the nerve-associated, neural crest-derived Schwann cell precursors (SCPs). Notably, we found that SCPs activate the autonomic marker PHOX2B while migrating along motor nerves towards the region of the dorsal aorta in wildtype embryos, suggesting that SCP differentiate into sympathetic neurons while still nerve-associated in motor-ablated embryos. Ligand-receptor prediction from single cell transcriptomic data coupled with functional studies identified Semaphorin 3A/3F as candidate motor nerve-derived signals influencing neural crest migration along axons. Thus, motor nerves control the placement of sympathoblasts and their subsequent axonal navigation during critical periods of sympathetic chain development.

developmental biology↗

bioRxiv2022

Cachd1 is a novel Frizzled- and LRP6-interacting protein required for neurons to acquire left-right asymmetric character

Neurons on left and right sides of the nervous system frequently show asymmetric properties but how these differences arise is poorly understood. Through a forward genetic screen in zebrafish, we find that loss of function of the transmembrane protein Cachd1 results in right-sided habenula neurons adopting left-sided character. Cachd1 is expressed in habenula neuron progenitors, functions symmetrically downstream of asymmetric environmental signals that determine laterality and influences timing of the normally left-right asymmetric patterns of neurogenesis. Unbiased screening for Cachd1 partners identified the Wnt co-receptor Frizzled7 and further biochemical and structural analysis revealed Cachd1 can bind simultaneously to Fzd proteins and Lrp6, bridging between these two Wnt co-receptors. Consistent with these structural studies, lrp6 mutant zebrafish show symmetric habenulae with left-sided character and epistasis experiments with other Wnt pathway genes support an in vivo role for Cachd1 in modulating Wnt pathway activity in the brain. Together, these studies identify Cachd1 as a conserved novel Wnt-receptor interacting protein with roles in regulating neurogenesis and neuronal identity.

developmental biology↗

bioRxiv2020

Notch signaling is a critical initiator of roof plate formation as revealed by the use of RNA profiling of the dorsal neural tube

The factors underlying establishment of the definitive roof plate (RP) and its segregation from neural crest (NC) and interneurons are unknown. We performed transcriptome analysis at trunk levels of quail embryos comparing the dorsal neural tube at premigratory NC and RP stages. This unraveled molecular heterogeneity between NC and RP stages, and within the RP itself. By implementing these genes, we asked whether Notch signaling is involved in RP development. First, we observed that Notch is active at the RP-interneuron interface. Furthermore, gain and loss of Notch function in quail and mouse embryos, respectively, revealed no effect on early NC behavior. Constitutive Notch activation caused a local downregulation of RP markers with a concomitant development of dI1 interneurons, as well as an ectopic upregulation of RP markers in the interneuron domain. Reciprocally, in mice lacking Notch activity both the RP and dI1 interneurons failed to form and this was associated with expansion of the dI2 population. Collectively, our results offer a new resource for defining specific cell types, and provide evidence that Notch is required to establish the definitive RP, and to determine the choice between RP and interneuron fates, but not the segregation of RP from NC. Summary statementA new set of genes involved in Notch-dependent roof plate formation is unraveled by transcriptome analysis.

developmental biology↗

bioRxiv2020

The GINS complex is required for the survival of rapidly proliferating retinal and tectal progenitor cells during zebrafish development

Efficient and accurate DNA replication is particularly critical in stem and progenitor cells for successful proliferation and survival. The replisome, an amalgam of protein complexes, is responsible for binding potential origins of replication, unwinding the double helix, and then synthesizing complimentary strands of DNA. According to current models, the initial steps of DNA unwinding and opening are facilitated by the CMG complex, which is composed of a GINS heterotetramer that connects Cdc45 with the mini-chromosome maintenance (Mcm) helicase. In this work, we provide evidence that in the absence of GINS function DNA replication is cell autonomously impaired, and we also show that gins1 and gins2 mutants exhibit elevated levels of apoptosis restricted to actively proliferating regions of the central nervous system (CNS). Intriguingly, our results also suggest that the rapid cell cycles during early embryonic development in zebrafish may not require the function of the GINS complex as neither Gins1 nor Gins2 seem to be present during these stages.

genetics↗

bioRxiv2018

Compensatory mechanisms render Tcf7l1a dispensable for eye formation despite its requirement in eye field specification

The vertebrate eye originates from the eyefield, a domain of cells specified by a small number of transcription factors. In this study, we show that Tcf7la is one such transcription factor that acts cell-autonomously to specify the eye field in zebrafish. Despite the much reduced eyefield in tcf7l1a mutants, these fish develop normal eyes revealing a striking ability of the eye to recover from a severe early phenotype. This robustness is not mediated through compensation by paralogous genes; instead, the smaller optic vesicle of tcf7l1a mutants shows delayed neurogenesis and continues to grow until it achieves approximately normal size. Although the developing eye is robust to the lack of Tcf7l1a function, it is sensitised to the effects of additional mutations. In support of this, a forward genetic screen identified mutations in hesx1, cct5 and gdf6a, which give synthetically enhanced eye specification or growth phenotypes when in combination with the tcf7l1a mutation.

developmental biology↗