bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transforming growth factor β3 induces cell death during the first stage of mammary gland involution
Authors: Nguyen Andrew V. , Pollard Jeffrey W. 
Published: April 2021

ABSTRACT
Involution of the mammary gland following weaning is divided into two distinct phases. Initially, milk stasis results in the induction of local factors that cause apoptosis in the alveolar epithelium. Secondly after a prolonged absence of suckling, the consequent decline in circulating lactogenic hormone concentrations initiates remodeling of the mammary gland to the virgin-like state. We have shown that immediately following weaning TGFβ3 mRNA and protein is rapidly induced in the mammary epithelium and that this precedes the onset of apoptosis. Unilateral inhibition of suckling and hormonal reconstitution experiments showed that TGFβ3 induction is regulated by milk stasis and not by the circulating hormonal concentration. Directed expression of TGFβ3 in the alveolar epithelium of lactating mice using a β-lactoglobulin promoter mobilized SMAD4 translocation to the nucleus and caused apoptosis of these cells, but not tissue remodeling. Transplantation of neonatal mammary tissue derived from TGFβ3 null mutant mice into syngenic hosts resulted in a significant inhibition of cell death compared to wild-type mice upon milk stasis. These results provide direct evidence that TGFβ3 is a local mammary factor induced by milk stasis that causes apoptosis in the mammary gland epithelium during involution.
Structural requirements for Notch signalling with Delta and Serrate during the development and patterning of the wing disc of Drosophila
Authors: Lawrence Nicola , Klein Thomas , Brennan Keith , Arias Alfonso Martinez 
Published: April 2021

Abstract
The Delta and Serrate proteins interact with the extracellular domain of the Notch receptor and initiate signalling through the receptor. The two ligands are very similar in structure and have been shown to be interchangeable experimentally; however, loss of function analysis indicates that they have different functions during development and analysis of their signalling during wing development indicates that the Fringe protein can discriminate between the two ligands. This raises the possibility that the signalling of Delta and Serrate through Notch requires different domains of the Notch protein. Here we have tested this possibility by examining the ability of Delta and Serrate to interact and signal with Notch molecules in which different domains had been deleted. This analysis has shown that EGF-like repeats 11 and 12, the RAM-23 and cdc10/ankyrin repeats and the region C-terminal to the cdc10/ankyrin repeats of Notch are necessary for both Delta and Serrate to signal via Notch. They also indicate, however, that Delta and Serrate utilise EGF-like repeats 24-26 of Notch for signalling, but there are significant differences in the way they utilise these repeats.
Dpp signaling thresholds in the dorsal ectoderm of the Drosophila embryo
Authors: Ashe Hilary L. , Mannervik Mattias , Levine Michael 
Published: April 2021

ABSTRACT
The dorsal ectoderm of the Drosophila embryo is subdivided into different cell types by an activity gradient of two TGFβ signaling molecules, Decapentaplegic (Dpp) and Screw (Scw). Patterning responses to this gradient depend on a secreted inhibitor, Short gastrulation (Sog) and a newly identified transcriptional repressor, Brinker (Brk), which are expressed in neurogenic regions that abut the dorsal ectoderm. Here we examine the expression of a number of Dpp target genes in transgenic embryos that contain ectopic stripes of Dpp, Sog and Brk expression. These studies suggest that the Dpp/Scw activity gradient directly specifies at least three distinct thresholds of gene expression in the dorsal ectoderm of gastrulating embryos. Brk was found to repress two target genes, tailup and pannier, that exhibit different limits of expression within the dorsal ectoderm. These results suggest that the Sog inhibitor and Brk repressor work in concert to establish sharp dorsolateral limits of gene expression. We also present evidence that the activation of Dpp/Scw target genes depends on the Drosophila homolog of the CBP histone acetyltransferase.
The homeodomain protein CePHOX2/CEH-17 controls antero-posterior axonal growth in C. elegans
Authors: Pujol Nathalie , Torregrossa Pascal , Ewbank Jonathan J. , Brunet Jean-François 
Published: April 2021

ABSTRACT
An essential aspect of a neuron’s identity is the pattern of its axonal projections. In C. elegans, axons extend either longitudinally or circumferentially in response to distinct molecular cues, some of which have been identified. It is currently unclear, however, how the differential capacity to respond to these cues is transcriptionally implemented in distinct neuronal subtypes. Here, we characterise a C. elegans paired-like homeobox gene, CePhox2/ceh-17, expressed in five head neurons, ALA and the 4 SIAs, all of which project axons towards the tail along the lateral and sublateral cords. Abrogation of ceh-17 function, while leaving intact many phenotypic traits of these neurons, disrupts their antero-posterior axonal elongation beyond the mid-body region. Conversely, ectopic expression of ceh-17 in the mechanoreceptors, several of which are known to pioneer their tract, leads to exaggerated longitudinal axonal outgrowth. Thus, ceh-17 is a novel gene involved in fasciculation-independent longitudinal axonal navigation.
Deletion of a silencer element disruptsH19imprinting independently of a DNA methylation epigenetic switch
Authors: Drewell Robert A. , Brenton James D. , Ainscough Justin F.-X. , Barton Sheila C. , Hilton Kathy J. , Arney Katharine L. , Dandolo Luisa , Surani M. Azim 
Published: April 2021

ABSTRACTThe H19 imprinted gene is silenced when paternally inherited and active only when inherited maternally. This is thought to involve a cis-acting control region upstream of H19 that is responsible for regulating a number of functions including DNA methylation, asynchronous replication of parental chromosomes and an insulator. Here we report on the function of a 1.2 kb upstream element in the mouse, which was previously shown to function as a bi-directional silencer in Drosophila. The cre-loxP-mediated targeted deletion of the 1.2 kb region had no effect on the maternal allele. However, there was loss of silencing of the paternal allele in many endodermal and other tissues. The pattern of expression was very similar to the expression pattern conferred by the enhancer elements downstream of H19. We could not detect an effect on the expression of the neighbouring imprinted Igf2 gene, suggesting that the proposed boundary element insulating this gene from the downstream enhancers was unaffected. Despite derepression of the paternal H19 allele, the deletion surprisingly did not affect the differential DNA methylation of the locus, which displayed an appropriate epigenetic switch in the parental germlines. Furthermore, the characteristic asynchronous pattern of DNA replication at H19 was also not disrupted by the deletion, suggesting that the sequences that mediate this were also intact. The silencer is therefore part of a complex cis-regulatory region upstream of the H19 gene and acts specifically to ensure the repression of the paternal allele, without a predominant effect on the epigenetic switch in the germline.
p57Kip2 regulates progenitor cell proliferation and amacrine interneuron development in the mouse retina
Authors: Dyer Michael A. , Cepko Constance L. 
Published: April 2021

ABSTRACT
A precise balance between proliferation and differentiation must be maintained during retinal development to obtain the correct proportion of each of the seven cell types found in the adult tissue. Cyclin kinase inhibitors can regulate cell cycle exit coincident with induction of differentiation programs during development. We have found that the p57Kip2 cyclin kinase inhibitor is upregulated during G1/G0 in a subset of retinal progenitor cells exiting the cell cycle between embryonic day 14.5 and 16.5 of mouse development. Retroviral mediated overexpression of p57Kip2 in embryonic retinal progenitor cells led to premature cell cycle exit. Retinae from mice lacking p57Kip2 exhibited inappropriate S-phase entry and apoptotic nuclei were found in the region where p57Kip2 is normally expressed. Apoptosis precisely compensated for the inappropriate proliferation in the p57Kip2-deficient retinae to preserve the correct proportion of the major retinal cell types. Postnatally, p57Kip2 was found to be expressed in a novel subpopulation of amacrine interneurons. At this stage, p57Kip2 did not regulate proliferation. However, perhaps reflecting its role during this late stage of development, animals lacking p57Kip2 showed an alteration in amacrine subpopulations. p57Kip2 is the first gene to be implicated as a regulator of amacrine subtype/subpopulation development. Consequently, we propose that p57Kip2 has two roles during retinal development, acting first as a cyclin kinase inhibitor in mitotic progenitor cells, and then playing a distinct role in neuronal differentiation.
Zebrafishkitmutation reveals primary and secondary regulation of melanocyte development during fin stripe regeneration
Authors: Rawls John F. , Johnson Stephen L. 
Published: April 2021

ABSTRACTFin regeneration in adult zebrafish is accompanied by reestablishment of the pigment stripes. To understand the mechanisms underlying fin stripe regeneration and regulation of normal melanocyte stripe morphology, we investigated the origins of melanocytes in the regenerating fin and their requirement for the kit receptor tyrosine kinase. Using pre-existing melanin as a lineage tracer, we show that most fin regeneration melanocytes develop from undifferentiated precursors, rather than from differentiated melanocytes. Mutational analysis reveals two distinct classes of regeneration melanocytes. First, an early regeneration class develops dependent on kit function. In the absence of kit function and kit-dependent melanocytes, a second class of melanocytes develops at later stages of regeneration. This late kit-independent class of regeneration melanocytes has little or no role in wild-type fin stripe development, thus revealing a secondary mode for regulation of fin stripes. Expression of melanocyte markers in regenerating kit mutant fins suggests that kit normally acts after mitf and before dct to promote development of the primary kit-dependent melanocytes. kit-dependent and kit-independent melanocytes are also present during fin stripe ontogeny in patterns similar to those observed during regeneration.
EGF receptor attenuates Dpp signaling and helps to distinguish the wing and leg cell fates inDrosophila
Authors: Kubota Kazumasa , Goto Satoshi , Eto Kazuhiro , Hayashi Shigeo 
Published: April 2021

ABSTRACTWing and leg precursors of Drosophila are recruited from a common pool of ectodermal cells expressing the homeobox gene Dll. Induction by Dpp promotes this cell fate decision toward the wing and proximal leg. We report here that the receptor tyrosine kinase EGFR antagonizes the wing-promoting function of Dpp and allows recruitment of leg precursor cells from uncommitted ectodermal cells. By monitoring the spatial distribution of cells responding to Dpp and EGFR, we show that nuclear transduction of the two signals peaks at different position along the dorsoventral axis when the fates of wing and leg discs are specified and that the balance of the two signals assessed within the nucleus determines the number of cells recruited to the wing. Differential activation of the two signals and the cross talk between them critically affect this cell fate choice.
sucker encodes a zebrafish Endothelin-1 required for ventral pharyngeal arch development
Authors: Miller Craig T. , Schilling, Thomas F. , Lee, Kyu-Ho , Parker Jewel , Kimmel Charles B. 
Published: April 2021

ABSTRACT
Mutation of sucker (suc) disrupts development of the lower jaw and other ventral cartilages in pharyngeal segments of the zebrafish head. Our sequencing, cosegregation and rescue results indicate that suc encodes an Endothelin-1 (Et-1). Like mouse and chick Et-1, suc/et-1 is expressed in a central core of arch paraxial mesoderm and in arch epithelia, both surface ectoderm and pharyngeal endoderm, but not in skeletogenic neural crest. Long before chondrogenesis, suc/et-1 mutant embryos have severe defects in ventral arch neural crest expression of dHAND, dlx2, msxE, gsc, dlx3 and EphA3 in the anterior arches. Dorsal expression patterns are unaffected. Later in development, suc/et-1 mutant embryos display defects in mesodermal and endodermal tissues of the pharynx. Ventral premyogenic condensations fail to express myoD, which correlates with a ventral muscle defect. Further, expression of shh in endoderm of the first pharyngeal pouch fails to extend as far laterally as in wild types. We use mosaic analyses to show that suc/et-1 functions nonautonomously in neural crest cells, and is thus required in the environment of postmigratory neural crest cells to specify ventral arch fates. Our mosaic analyses further show that suc/et-1 nonautonomously functions in mesendoderm for ventral arch muscle formation. Collectively our results support a model for dorsoventral patterning of the gnathostome pharyngeal arches in which Et-1 in the environment of the postmigratory cranial neural crest specifies the lower jaw and other ventral arch fates.
Maternal undernutrition during the preimplantation period of rat development causes blastocyst abnormalities and programming of postnatal hypertension
Authors: Kwong Wing Yee , Wild Arthur E. , Roberts Paul , Willis Antony C. , Fleming Tom P. 
Published: April 2021

ABSTRACT
Epidemiological studies have indicated that susceptibility of human adults to hypertension and cardiovascular disease may result from intrauterine growth restriction and low birth weight induced by maternal undernutrition. Although the ‘foetal origins of adult disease’ hypothesis has significant relevance to preventative healthcare, the origin and biological mechanisms of foetal programming are largely unknown. Here, we investigate the origin, embryonic phenotype and potential maternal mechanisms of programming within an established rat model. Maternal low protein diet (LPD) fed during only the preimplantation period of development (0-4.25 days after mating), before return to control diet for the remainder of gestation, induced programming of altered birthweight, postnatal growth rate, hypertension and organ/body-weight ratios in either male or female offspring at up to 12 weeks of age. Preimplantation embryos collected from dams after 0-4.25 days of maternal LPD displayed significantly reduced cell numbers, first within the inner cell mass (ICM; early blastocyst), and later within both ICM and trophectoderm lineages (mid/late blastocyst), apparently induced by a slower rate of cellular proliferation rather than by increased apoptosis. The LPD regimen significantly reduced insulin and essential amino acid levels, and increased glucose levels within maternal serum by day 4 of development. Our data indicate that long-term programming of postnatal growth and physiology can be induced irreversibly during the preimplantation period of development by maternal protein undernutrition. Further, we propose that the mildly hyperglycaemic and amino acid-depleted maternal environment generated by undernutrition may act as an early mechanism of programming and initiate conditions of ‘metabolic stress’, restricting early embryonic proliferation and the generation of appropriately sized stem-cell lineages.
Effect of single and compound knockouts of estrogen receptors α (ERα) and β (ERβ) on mouse reproductive phenotypes
Authors: Dupont Sonia , Krust Andrée , Gansmuller Anne , Dierich Andrée , Chambon Pierre , Mark Manuel 
Published: April 2021

ABSTRACT
The functions of estrogen receptors (ERs) in mouse ovary and genital tracts were investigated by generating null mutants for ERα (ERαKO), ERβ (ERβKO) and both ERs (ERαβKO). All ERαKO females are sterile, whereas ERβKO females are either infertile or exhibit variable degrees of subfertility. Mast cells present in adult ERαKO and ERαβKO ovaries could participate in the generation of hemorrhagic cysts. Folliculogenesis proceeds normally up to the large antral stage in both ERαKO and ERβKO adults, whereas large antral follicles of ERα+/−/ERβKO and ERαβKO adults are markedly deficient in granulosa cells. Similarly, prematurely developed follicles found in prepubertal ERαKO ovaries appear normal, but their ERαβKO counterparts display only few granulosa cell layers. Upon superovulation treatment, all prepubertal ERαKO females form numerous preovulatory follicles of which the vast majority do not ovulate. The same treatment fails to elicit the formation of preovulatory follicles in half of the ERβKO mice and in all ERα+/−/ERβKO mice. These and other results reveal a functional redundancy between ERα and ERβ for ovarian folliculogenesis, and strongly suggest that (1) ERβ plays an important role in mediating the stimulatory effects of estrogens on granulosa cell proliferation, (2) ERα is not required for follicle growth under wild type conditions, while it is indispensable for ovulation, and (3) ERα is also necessary for interstitial glandular cell development. Our data also indicate that ERβ exerts some function in ERαKO uterus and vagina. ERαβKO granulosa cells localized within degenerating follicles transform into cells displaying junctions that are unique to testicular Sertoli cells. From the distribution pattern of anti-Müllerian hormone (AMH) in ERαβKO ovaries, it is unlikely that an elevated AMH level is the cause of Sertoli cell differentiation. Our results also show that cell proliferation in the prostate and urinary bladder of old ERβKO and ERαβKO males is apparently normal.
Independent regulation of Dlx2 expression in the epithelium and mesenchyme of the first branchial arch
Authors: Thomas Bethan L. , Liu Jen Kuei , Rubenstein John L. R. , Sharpe Paul T. 
Published: April 2021

ABSTRACT
Dlx2, a member of the distal-less gene family, is expressed in the first branchial arch, prior to the initiation of tooth development, in distinct, non-overlapping domains in the mesenchyme and the epithelium. In the mesenchyme Dlx2 is expressed proximally, whereas in oral epithelium it is expressed distally. Dlx2 has been shown to be involved in the patterning of the murine dentition, since loss of function of Dlx1 and Dlx2 results in early failure of development of upper molar teeth. We have investigated the regulation of Dlx2 expression to determine how the early epithelial and mesenchymal expression boundaries are maintained, to help to understand the role of these distinct expression domains in patterning of the dentition.
Transgenic mice produced with a lacZ reporter construct, containing 3.8 kb upstream sequence of Dlx2, led to the mapping of regulatory regions driving epithelial but not mesenchymal expression in the first branchial arch. We show that the epithelial expression of Dlx2 is regulated by planar signalling by BMP4, which is coexpressed in distal oral epithelium. Mesenchymal expression is regulated by a different mechanism involving FGF8, which is expressed in the overlying epithelium. FGF8 also inhibits expression of Dlx2 in the epithelium by a signalling pathway that requires the mesenchyme. Thus, the signalling molecules BMP4 and FGF8 provide the mechanism for maintaining the strict epithelial and mesenchymal expression domains of Dlx2 in the first arch.
Induction and differentiation of the zebrafish heart requires fibroblast growth factor 8 (fgf8/acerebellar)
Authors: Reifers Frank , Walsh Emily C. , Léger Sophie , Stainier Didier Y. R. , Brand Michael 
Published: April 2021

ABSTRACT
Vertebrate heart development is initiated from bilateral lateral plate mesoderm that expresses the Nkx2.5 and GATA4 transcription factors, but the extracellular signals specifying heart precursor gene expression are not known. We describe here that the secreted signaling factor Fgf8 is expressed in and required for development of the zebrafish heart precursors, particularly during initiation of cardiac gene expression. fgf8 is mutated in acerebellar (ace) mutants, and homozygous mutant embryos do not establish normal circulation, although vessel formation is only mildly affected. In contrast, heart development, in particular of the ventricle, is severely abnormal in acerebellar mutants. Several findings argue that Fgf8 has a direct function in development of cardiac precursor cells: fgf8 is expressed in cardiac precursors and later in the heart ventricle. Fgf8 is required for the earliest stages of nkx2.5 and gata4, but not gata6, expression in cardiac precursors. Cardiac gene expression is restored in acerebellar mutant embryos by injecting fgf8 RNA, or by implanting a Fgf8-coated bead into the heart primordium. Pharmacological inhibition of Fgf signalling during formation of the heart primordium phenocopies the acerebellar heart phenotype, confirming that Fgf signaling is required independently of earlier functions during gastrulation. These findings show that fgf8/acerebellar is required for induction and patterning of myocardial precursors.
Regulation of neurogenesis by interactions between HEN1 and neuronal LMO proteins
Authors: Bao Jianxin , Talmage David A. , Role Lorna W. , Gautier Jean 
Published: April 2021

ABSTRACT
Basic-helix-loop-helix transcription factors regulate neurogenesis and neuronal differentiation by as yet unknown mechanisms. We show that an embryonic neuronal-specific basic-helix-loop-helix protein, HEN1 (also known as NSCL1 or NHLH), interacts with ‘LIM only’ proteins. Examination of the expression patterns of XHEN1 and XLMO-3, the Xenopus homologues of these human genes, reveals extensive overlap during early neurogenesis: at the onset of gastrulation on the dorsal side of the blastopore lip and, subsequently, in the prospective neural plate. Binding of XLMO-3 increases the transcriptional activity of XHEN1 in vivo. Co-expression of these two genes in Xenopus embryos induces a cascade of expression of neuronal-specific basic-helix-loop-helix proteins that leads to neuronal differentiation. We propose that XHEN1, in concert with XLMO-3, is a critical regulator of neurogenesis.