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bioRxiv2018

Thyroid hormone modulation during zebrafish development recapitulates evolved diversity in danionin jaw protrusion mechanics

One of three vertebrates belongs to a fish lineage for which protrusile jaws are a synapomorphy. Identifying the developmental determinants of protrusion ability will improve our understanding of an important area of evolutionary diversification. The high water viscosities experienced by tiny fish larvae inhibit the viability of protrusile jaws. In the zebrafish protrusion does not arise until after metamorphosis. Fish metamorphosis typically includes significant changes in trophic morphology, accompanies a shift in feeding niche and coincides with increased thyroid hormone production. We tested whether thyroid hormone affects the development of zebrafish feeding mechanics. We found that it affected all developmental stages examined, but that these effects were most pronounced after metamorphosis. Thyroid hormone levels affected the development of jaw morphology, feeding mechanics, shape variation and cranial ossification. Adult zebrafish utilize protrusile jaws, but an absence of thyroid hormone eliminated postmetamorphic remodeling of the premaxilla and the premaxillary structure that permits protrusion never formed. The premaxillae of late juvenile and adult zebrafish are similar to those found in the adults of other Danio species. Premaxillae from early juvenile zebrafish and hypothyroid adult zebrafish resemble those from adults in the genera Danionella, Devario and Microdevario that show little to no jaw protrusion.

developmental biology↗

bioRxiv2018

Nodal and Eph signalling relay drives the transition between apical constriction and apico-basal shortening during ascidian endoderm invagination

Gastrulation is the first major morphogenetic event during animal embryogenesis. Ascidian gastrulation starts with the invagination of 10 endodermal precursor cells between the 64- and late 112-cell stages. This process occurs in the absence of endodermal cell division and in two steps, driven by myosin-dependent contractions of the acto-myosin network. First, endoderm precursors constrict their apex. Second, they shorten apico-basally, while retaining small apical surfaces, thereby causing invagination. The mechanisms controlling the endoderm mitotic delay, the step 1 to step 2 transition, and apico-basal shortening have remained elusive. Here, we demonstrate the conserved role during invagination of Nodal and Eph signalling in two distantly related ascidian species (Phallusia mammillata and Ciona intestinalis). We show that the transition to step 2 is controlled by Nodal relayed by Eph signalling and that Eph signalling has a Nodal-independent role in mitotic delay. Interestingly, both Nodal and Eph signals are dispensable for endodermal germ layer fate specification. Summary statementIdentification of a regulatory developmental signalling sub-network driving endoderm cell shape changes during ascidian endoderm invagination, not involved in cell fate specification.

developmental biology↗

bioRxiv2018

Hox genes limit germ cell formation in the short germ insect Gryllus bimaculatus.

Hox genes are conserved transcription factor-encoding genes that specify the identity of body regions in bilaterally symmetrical animals. In the cricket Gryllus bimaculatus, a member of the hemimetabolous insect group Orthoptera, the induction of a subset of mesodermal cells to form the primordial germ cells (PGCs) is restricted to the second through the fourth abdominal segments (A2-A4). In numerous insect species, the Hox genes Sex-combs reduced (Scr), Antennapedia (Antp), Ultrabithorax (Ubx) and abdominal-A (abd-A) jointly regulate the identities of middle and posterior body segments, suggesting that these genes may restrict PGC formation to specific abdominal segments in G. bimaculatus. Here we show that all of these Hox genes, either individually or in segment-specific combinations, restrict PGC formation. Our data provides evidence for a segmental Hox code used to regulate the placement of PGC formation, reminiscent of the segmental Hox codes used in other arthropod groups to establish other aspects of segmental identity. These data also provide, to our knowledge, the first evidence for this ancient group of genes in determining PGC placement within the context of axial patterning in any animal studied thus far.

developmental biology↗

bioRxiv2018

Mutual transcriptional repression between Gli3 and Hox13 genes determines the anterior-posterior asymmetry of the autopod

In the present study we have investigated the molecular causes of the absence of digit 1 in the Hoxa13 mutant and why the absence of Hoxa13 protein, whose expression spans the entire autopod, specifically impacts the anterior-most digit. We show that in the absence of Hoxa13, the expression of Hoxd13 does not extend into the anterior mesoderm consequently leaving the presumptive territory of digit1 devoid of distal Hox expression and providing an explanation for the agenesis of digit 1. We provide compelling evidence that the lack of Hoxd13 transcription in the anterior mesoderm is due to increased Gli3R activity, in turn resulting from the loss of transcriptional repression exerted by Hoxa13 on Gli3. Our results are compatible with a mutual transcriptional repression between Gli3 and Hox13 genes that determines the anterior-posterior asymmetry of the autopod.

developmental biology↗

bioRxiv2018

The Dlg-module and clathrin-mediated endocytosis regulate EGFR signaling and cyst cell-germline coordination in the Drosophila testis

Tissue homeostasis and repair relies on proper communication of stem cells and their differentiating daughters with the local tissue microenvironment. In the Drosophila male germline adult stem cell lineage, germ cells proliferate and progressively differentiate enclosed in supportive somatic cyst cells, forming a small organoid, the functional unit of differentiation. Here we show that cell polarity and vesicle trafficking influence signal transduction in cyst cells, with profound effects on the germ cells they enclose. Our data suggest that both the cortical components Dlg, Scrib, Lgl and the clathrin-mediated endocytic (CME) machinery downregulate EGFR signaling. Knockdown of dlg, scrib, lgl or CME components in cyst cells resulted in germ cell death, similar to increased signal transduction via the EGFR, while lowering EGFR or downstream signaling components rescued the defects. This work provides new insights on how cell polarity and endocytosis cooperate to regulate signal transduction and sculpt developing tissues.

developmental biology↗

bioRxiv2018

Over-expression of Hsp83 in grossly depleted hsrω lncRNA background causes synthetic lethality and l(2)gl phenocopy in Drosophila

We examined interactions between Hsp83 and hsr{omega} lncRNAs in hsr{omega}66 Hsp90GFP homozygotes, which almost completely lack hsr{omega} lncRNAs but over-express Hsp83. All +/+; hsr{omega}66 Hsp90GFP progeny died before third instar. Rare Sp/CyO; hsr{omega}66 Hsp90GFP reached third instar stage but phenocopied l(2)gl mutants, dying after prolonged larval life, becoming progressively bulbous and transparent with enlarged brain. Additionally, ventral ganglia were elongated. However, hsr{omega}66 Hsp90GFP/TM6B heterozygotes, carrying +/+ or Sp/CyO second chromosomes, developed normally. Total RNA sequencing (+/+, +/+; hsr{omega}66/hsr{omega}66, Sp/CyO; hsr{omega}66/hsr{omega}66, +/+; Hsp90GFP/Hsp90GFP, and Sp/CyO; hsr{omega}66 Hsp90GFP/hsr{omega}66 Hsp90GFP late third instar larvae) revealed similar effects on many genes in hsr{omega}66 and Hsp90GFP homozygotes. Besides additive effect on many of them, numerous additional genes were affected in Sp/CyO; hsr{omega}66 Hsp90GFP larvae, with l(2)gl and several genes regulating CNS being highly down-regulated in surviving Sp/CyO; hsr{omega}66 Hsp90GFP larvae, but not in hsr{omega}66 or Hsp90GFP single mutants. Hsp83 binds at these gene promoters. Several omega speckle associated hnRNPs too may bind with these genes and transcripts. Hsp83-hnRNP interactions are also known. Thus, elevated Hsp83 in altered hnRNP distribution and dynamics, following absence of hsr{omega} lncRNAs and omega speckles, background can severely perturb regulatory circuits with unexpected consequences, including down-regulation of tumor suppressor gene like l(2)gl.

developmental biology↗

bioRxiv2018

Loss of zebrafish ctnnd2b results in disorganised forebrain neuron clusters

Delta catenin (CTNND2) is an adhesive junction associated protein belonging to the family of p120ct catenins. It is located on the short arm of chromosome 5, a region deleted in Cri-du-chat syndrome. Heterozygous loss of CTNND2 function has been linked to autism, schizophrenia, and mild intellectual disability with or without dyslexia-like learning difficulties. To date, most functional studies have focused on homozygous loss of the gene, contradictory to the dominant effect of loss of a single allele observed in neurodevelopmental disorders. Here we show that heterozygous loss of ctnnd2b results in a disorganisation and imbalance of neuronal subtypes in forebrain specific regions. Using the zebrafish model, we show that CRISPR/Cas9-induced loss of ctnnd2b but not ctnnd2a results in an increase in isl1-expressing cells and a local reduction of GABA expressing neurons in the optic recess region of the embryonic zebrafish forebrain. Using time-lapse analysis, we found that the disorganised distribution of is1l-expressing forebrain neurons was not due to migration defects, but rather an increase in the number of isl1-GFP neurons in the optic recess region. Upon closer analysis, these neurons appear disorganised and show an altered morphology and orientation. Overall this data suggests that ctnnd2 may affect the differentiation cascade of neuronal subtypes in specific regions of the vertebrate brain.

developmental biology↗

bioRxiv2018

Wdr5, Brca1 and Bard1 link the DNA damage response to the mesenchymal-to-epithelial transition during early reprogramming.

Differentiated cells are epigenetically stable, but can be reprogrammed to pluripotency by expression of the OSKM transcription factors. Despite significant effort, relatively little is known about the cellular requirements for reprogramming and how they affect the properties of induced pluripotent stem cells (iPSC). We have performed high-content screening with siRNAs targeting 300 chromatin-associated factors. We used colony features, such as size and shape, as well as strength and homogeneity of marker gene expression to define five colony phenotypes in early reprogramming. We identified transcriptional signatures associated with these phenotypes in a secondary RNA sequencing screen. One of these phenotypes involves large colonies and an early block of reprogramming. Double knockdown epistasis experiments of the genes involved, revealed that Brca1, Bard1 and Wdr5 functionally interact and are required for both the DNA damage response and the mesenchymal-to-epithelial transition (MET), linking these processes. Moreover, the data provide a resource on the role of chromatin-associated factors in reprogramming and underline colony morphology as an important high dimensional readout for reprogramming quality.

developmental biology↗

bioRxiv2018

The GATOR complex regulates an essential response to meiotic double-stranded breaks in Drosophila

The TORC1 inhibitor GATOR1/SEACIT controls meiotic entry and early meiotic events in yeast. However, how metabolic pathways influence meiotic progression in metazoans remains poorly understood. Here we report that the TORC1 regulators GATOR1 and GATOR2 mediate a response to meiotic double-stranded breaks (DSBs) during Drosophila oogenesis. We find that meiotic DSBs trigger the activation of a GATOR1 dependent pathway that downregulates TORC1 activity in the female germline. In GATOR1 mutants, high TORC1 activity results in the delayed repair of meiotic DSBs and the hyperactivation of p53. Conversely, the GATOR2 component Mio is required to attenuate GATOR1 activity, to ensure that meiotic DSBs do not trigger a permanent growth arrest. Unexpectedly, we found that GATOR1 inhibits retrotransposon expression in the presence of meiotic DSBs in a pathway that functions in parallel to p53. Our studies have revealed a link between the GATOR complex, the repair of meiotic DSBs and retrotransposon expression

developmental biology↗

bioRxiv2018

wnt4a Promotes Female Development and Reproductive Duct Elongation in Zebrafish

In laboratory strains of zebrafish, sex determination occurs in the absence of a typical sex chromosome and it is not known what regulates the proportion of animals that develop as male or female. Many sex determination and differentiation genes that act downstream of a sex chromosome are well conserved among vertebrates, but studies that test their contribution to this process have mostly been limited to mammalian models. In mammals, WNT4 is a signaling ligand that is essential for ovary and Mullerian duct development, where it function, in part, to antagonize the male-promoting FGF9 signal. Wnt4 is highly conserved in non-mammalian vertebrates, but it is not known if Wnt4 plays a role in sex determination and/or the differentiation of sex organs outside of mammals. This is an especially interesting question in teleost, such as zebrafish, because they lack an Fgf9 ortholog. Here we show that wnt4a is the ortholog of mammalian Wnt4, and that wnt4b was present in the last common ancestor of humans and zebrafish, but was lost in mammals. We found that wnt4a is expressed in the somatic cells of juvenile gonads during the time sex determination likely occurs. We show that wnt4a loss-of-function mutants develop predominantly as males and conclude that wnt4a activity promotes female sex determination in zebrafish. Additionally, both male and female wnt4a mutants are sterile because their reproductive ducts do not connect to the vent, where wnt4a is normally expressed. Yet when dissected from homozygous wnt4a mutant gonads, both sperm and eggs can produce fertile offspring. Together these results strongly argue that Wnt4a is a conserved regulator of female sex determination and reproductive duct development in non-mammalian vertebrates.\n\nSUMMARYWnt4 is a key regulator of ovary development in mammals, but it is not known if it plays a similar role in other vertebrates. Here we show that zebrafish wnt4a is the ortholog of mammalian Wnt4. We show that wnt4a is expressed in zebrafish somatic gonad cells during the time sex determination likely occurs. Through analysis of wnt4a mutants, we show that Wnt4a promotes female sex determination and the development of the male and female reproductive. We conclude that Wnt4/Wnt4a is likely a conserved regulator of ovarian and reproductive duct development in all vertebrates

developmental biology↗

bioRxiv2018

Integrin-mediated attachment of the blastoderm to the vitelline envelope impacts gastrulation of insects

During gastrulation, physical forces reshape the simple embryonic tissue to form a complex body plan of multicellular organisms1. These forces often cause large-scale asymmetric movements of the embryonic tissue2,3. In many embryos, the tissue undergoing gastrulation movements is surrounded by a rigid protective shell4,5. While it is well recognized that gastrulation movements depend on forces generated by tissue-intrinsic contractility6,7, it is not known if interactions between the tissue and the protective shell provide additional forces that impact gastrulation. Here we show that a particular part of the blastoderm tissue of the red flour beetle Tribolium castaneum tightly adheres in a temporally coordinated manner to the vitelline envelope surrounding the embryo. This attachment generates an additional force that counteracts the tissue-intrinsic contractile forces to create asymmetric tissue movements. Furthermore, this localized attachment is mediated by a specific integrin, and its knock-down leads to a gastrulation phenotype consistent with complete loss of attachment. Moreover, analysis of another integrin in the fruit fly Drosophila melanogaster suggests that gastrulation in this organism also relies on adhesion between the blastoderm and the vitelline. Together, our findings reveal a conserved mechanism whereby the spatiotemporal pattern of tissue adhesion to the vitelline envelope provides controllable counter-forces that shape gastrulation movements in insects.

developmental biology↗

bioRxiv2018

Notch signalling maintains Hedgehog responsiveness via a Gli-dependent mechanism during spinal cord patterning in zebrafish

Spinal cord patterning is orchestrated by multiple cell signalling pathways. Neural progenitors are maintained by Notch signalling, whereas ventral neural fates are specified by Hedgehog (Hh) signalling. However, how dynamic interactions between Notch and Hh signalling drive the precise pattern formation is still unknown. We applied the PHRESH (PHotoconvertible REporter of Signalling History) technique to analyse cell signalling dynamics in vivo during zebrafish spinal cord development. This approach reveals that Notch and Hh signalling display similar spatiotemporal kinetics throughout spinal cord patterning. Notch signalling functions upstream to control Hh response of neural progenitor cells. Using gain- and loss-of-function tools, we demonstrate that this regulation occurs not at the level of upstream regulators or primary cilia, but rather at the level of Gli transcription factors. Our results indicate that Notch signalling maintains Hh responsiveness of neural progenitors via a Gli-dependent mechanism in the spinal cord.

developmental biology↗

bioRxiv2018

Gpr63 is a novel modifier of microcephaly in Ttc21b mouse mutants.

The primary cilium is a critical signaling center for proper embryonic development. Previous studies have demonstrated that mice lacking Ttc21b have impaired retrograde trafficking within the cilium and multiple organogenesis phenotypes, including microcephaly. Interestingly, the severity of the microcephaly in Ttc21baln/aln homozygous null mutants is considerably affected by the genetic background. Ttc21baln/aln mutants on an FVB/NJ background develop a forebrain significantly smaller than mutants on a C57BL/6J background. We performed a Quantitative Trait Locus (QTL) analysis to identify potential genetic modifiers and identified two regions linked to differential forebrain size: modifier of alien QTL1 (Moaq1) on chromosome 4 at 27.8 Mb and Moaq2 on chromosome 6 at 93.6 Mb. These QTLs were validated by constructing congenic strains. Further analysis of Moaq1 identified a brain specific orphan G-protein coupled receptor (GPCR), Gpr63, as a candidate gene. We identified a SNP between the FVB and B6 strains in Gpr63, which creates a missense mutation predicted to be deleterious in the FVB protein. We first demonstrated that Gpr63 can localize to the cilium and then used CRISPR-Cas9 genome editing to create FVB congenic mice with the B6 sequence of Gpr63 and a deletion allele leading to a truncation of the GPR63 C-terminal tail. These alleles genetically interact with Ttc21baln/aln, validating Gpr63 as a forebrain modifier of Ttc21b and strongly supporting Gpr63 as the variant causal gene (i.e., the quantitative trait gene, QTG) for Moaq1.

developmental biology↗

bioRxiv2018

A specific Ret receptor isoform is required for pioneer axon outgrowth and growth cone dynamics

In many cases, axon growth and guidance are driven by pioneer axons, the first axons to grow in a particular region. Despite their dynamic pathfinding capabilities and developmental importance, there are very few pioneer neuron specific markers and thus their in vivo identification and functional interrogation have been difficult. We found that a Ret receptor isoform, Ret51, is highly enriched in peripheral sensory pioneer neurons and is required for pioneer axon outgrowth. Ret null mutant pioneer neurons differentiate normally; however, they displayed defects in growth cone morphology and formation of filopodia before pioneer axon extension prematurely halts. We also demonstrate loss-of-function of a retrograde cargo adaptor, JNK-interacting protein 3 (Jip3), phenocopied many of these axonal defects. We further found that loss of Jip3 led to accumulation of activated Ret receptor in pioneer growth cones, indicating a failure in the clearance of activated Ret from growth cones. Using an axon sever approach as well as in vivo analysis of axonal transport, we showed Jip3 specifically mediates retrograde, but not anterograde, transport of activated Ret51. Finally, live imaging revealed that Jip3 and Ret51 were retrogradely co-transported in pioneer axons, suggesting Jip3 functions as an adapter for retrograde transport of Ret51. Taken together, these results identify Ret51 as a molecular marker of pioneer neurons and elucidate an important isoform-specific role for Ret51 in axon growth and growth cone dynamics during development.

developmental biology↗

bioRxiv2018

GPR17 is an Essential Component of the Negative Feedback Loop of the Sonic Hedgehog Signalling Pathway in Neural Tube Development

Dorsal-ventral pattern formation of the neural tube is regulated by temporal and spatial activities of extracellular signalling molecules. Sonic hedgehog (Shh) assigns ventral neural subtypes via activation of the Gli transcription factors. Shh activity changes dynamically during neural differentiation, but the mechanisms responsible for regulating this dynamicity are not fully understood. Here we show that the P2Y-type G-protein coupled receptor GPR17 is involved in temporal regulation of the Shh signal. GPR17 was expressed in the ventral progenitor regions of the neural tube and acted as a negative regulator of the Shh signal in chick embryos. While the activation of the GPR17-related signal inhibited ventral identity, perturbation of GPR17 expression led to aberrant expansion of ventral neural domains. Notably, perturbation of GPR17 expression partially inhibited the negative feedback of Gli activity. Moreover, GPR17 increased cAMP activity, suggesting that it exerts its function by inhibiting the processing of Gli3 protein. GPR17 also negatively regulated Shh signalling in neural cells differentiated from mouse embryonic stem cells, suggesting that GPR17 function is conserved among different organisms. Our results demonstrate that GPR17 is a novel negative regulator of Shh signalling in a wide range of cellular contexts.\n\nAuthor SummaryDuring neural development, determination of cell fate and the progress of differentiation are regulated by extracellular signal molecules, including Sonic Hedgehog (Shh). Shh forms a gradient within the embryonic organ of the central nervous system, or the neural tube, and a variety of cells are produced corresponding to the concentration. While the signal concentration is critical for cell fate, recent studies have revealed that the intracellular signal intensity does not always correspond to the Shh concentration. Rather, the intracellular signal intensity changes over time. Importantly, the signal intensity peaks and gradually decreases thereafter, and the half-life of the Shh signal contributes to the cell fate determination. However, the mechanisms for this temporal change are not fully understood.\n\nBy using chick embryos and mouse embryonic stem cells as model systems, we demonstrate that the G-protein coupled receptor, GPR17, is an essential regulator for the negative feedback of the Shh signal during neural development. While GPR17 gene expression is induced by the Shh signal, GPR17 perturbs the Shh signalling pathway. This negative function of GPR17 on the Shh signal is conserved among different vertebrate species. The collective data demonstrate that GPR17 is a negative regulator for the Shh signalling pathway in a wide range of the cellular contexts.

developmental biology↗

bioRxiv2018

Cdh2 coordinates Myosin-II dependent internalisation of the zebrafish neural plate

Tissue internalisation is a key morphogenetic mechanism by which embryonic tissues generate complex internal organs and a number of studies of epithelia have outlined a general view of tissue internalisation. Here we have used quantitative live imaging and mutant analysis to determine whether similar mechanisms are responsible for internalisation in a tissue that apparently does not have a typical epithelial organisation - the zebrafish neural plate. We found that although zebrafish embryos begin neurulation without a conventional epithelium, medially located neural plate cells adopt strategies typical of epithelia in order to constrict their dorsal surface membrane during cell internalisation. Furthermore, we show that Myosin-II activity is a significant driver of this transient cell remodeling which also depends on Cdh2 (N-cadherin). Abrogation of Cdh2 results in defective Myosin-II distribution, mislocalised internalisation events and defective neural plate morphogenesis. Our work suggests Cdh2 coordinates Myosin-II dependent internalisation of the zebrafish neural plate.

developmental biology↗

bioRxiv2018

The origin and evolution of acetylcholine signaling through AchRs in metazoans

BackgroundAcetylcholine is a cell signaling molecule that has been identified in plants, bacteria, and metazoans to play multiple roles in cells and as a neurotransmitter capable of exciting both neurons and muscle. While cell-cell communication activity has been reported in all phyla that have been investigated, its role as a neurotransmitter is less clear. Work within cnidarians implies that neurotransmitter activity emerged within or prior to the emergence of the cnidarian-bilaterian ancestor, but whether or not it is able to excite both muscles and neurons has not been addressed.\n\nResultsTo investigate the evolution of acetylcholine signaling we characterized the expression pattern of acetylcholine receptors (AchRs) and the neurotransmitter activity of acetylcholine in Nematostella vectensis. Expression patterns for 13 of the 21 known NvAchRs are consistent with acetylcholine acting as a cell signaling molecule and a neurotransmitter in neurons, muscles, or both. To dissect neurotransmitter activity we investigated the mechanism by which acetylcholine activates tentacular contractions in Nematostella. Tentacular contractions induced by application of acetylcholine are suppressed by inactivating voltage gated sodium channels with lidocaine indicating that acetylcholine specifically activates neurons in the tentacular contractile circuit.\n\nConclusionOur results verify that acetylcholines neurotransmitter activity emerged prior to cnidarian-bilaterian divergence and that non-neuronal roles were likely retained in Nematostella. Additionally, we found no evidence to support a muscle activating role for acetylcholine indicating that its role in muscle excitability evolved during bilaterian evolution.

developmental biology↗

bioRxiv2018

Differential expression and homotypic enrichment of a classic Cadherin directs tissue-level contractile asymmetry during neural tube closure

Embryos pattern force generation at tissue boundaries during morphogenesis, but how they do so remains poorly understood. Here we show how tissue-specific expression of the type II cadherin, Cadherin2 (hereafter Cad2), patterns actomyosin contractility along the neural/epidermal (Ne/Epi) boundary to drive zippering and neural tube closure in the basal chordate, Ciona robusta. Cad2 is differentially expressed and homotypically enriched in neural cells along the Ne/Epi boundary, where RhoA and Myosin are activated during zipper progression. Equalizing Cad2 expression across the Ne/Epi boundary inhibits RhoA/Myosin activation and zipper progression, while creating ectopic Cad2 expression boundaries is sufficient to direct RhoA/Myosin activity to those boundaries. We show that Cad2 polarizes RhoA activity by sequestering the Rho GTPase activating protein, Gap21/23, to homotypic junctions, which in turn redirects RhoA/Myosin activity to heterotypic Ne/Epi junctions. By activating Myosin II along Ne/Epi junctions ahead of zipper and inhibiting Myosin II at new Ne/Ne junctions behind zipper, Cad2 promotes tissue level contractile asymmetry to drive zipper progression.

developmental biology↗