bluuebunny/crossref_metadata_2025_split huggingface dataset:
Untangling Sources of Phenotypic Variation Characterizing the Craniofacial Disease Holoprosencephaly
Authors: Lainoff Alexis , Young Nathan , Hallgrimsson Benedikt , Marcucio Ralph 
Published: June 2021

Holoprosencaphly (HPE)—a craniofacial disorder in which the forebrain fails to develop into two hemispheres and the midface does not fully form—is characterized by a broad spectrum of severity. Phenotypes range from very mild midfacial narrowing to cyclopia. Mutations in Sonic hedgehog (SHH) and in SHH signaling pathway members are known to underlie HPE; however, the source of the highly variable craniofacial morphology manifesting in the HPE patient population is not understood. Previous research in a chick model suggests that reduced SHH‐signaling in the brain correlates with a continuous distribution of HPE‐like phenotypes, and that very small modifications in ligand concentration can result in highly heterogeneous morphologies. Here, we are probing the origins of morphological variation in a genetic mouse model. Although humans heterozygous for SHH mutations exhibit the full spectrum of HPE, mice heterozygous for Shh do not exhibit even mild HPE although homozygous mutants are cyclopic. Mice homozygous for mutations in the SHH‐signaling pathway member low‐density lipoprotein receptor‐related protein (Lrp) 2 however exhibit mild to severe forms of HPE, and are therefore a better model for examining sources of variation. LRP2 is an endocytic receptor required to induce proper SHH signaling in the forebrain. We used geometric morphometric analysis to quantify the shape of embryos with sequential, genetic loss of Shh and Lrp2 alleles, and qPCR was used to assess SHH signaling pathway activation. We found that there is no statistically significant difference in shape among wild‐type, Lrp2+/−, Shh+/−, and Lrp2+/−;Shh+/− embryos, while Lrp2−/− and Lrp2−/−;Shh+/− embryos diverged from the group, exhibiting a more narrow midface. Interestingly, there was increased phenotypic variance in Lrp2−/− and Lrp2−/−;Shh+/− embryos in comparison to the other genotypes, with a greater increase in variance seen in the Lrp2−/−;Shh+/− group. Our results support the hypothesis that very slight modifications to SHH pathway activation can yield large amounts of phenotypic variation.Support or Funding InformationThis work is supported by NIH/NIDCR‐R01DE018234, ‐R01DE019638, ‐T32DE730619, ‐F31DE02579001.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Identification of a Novel Vomer Phenotype in the Fgfr2cC342Y/+ Mouse Model of Crouzon Syndrome
Authors: Lesciotto Kate M. , Motch Perrine Susan M. , Kawasaki Kazuhiko , Richtsmeier Joan T. 
Published: June 2021

Crouzon syndrome has been linked with several FGFR2 mutations, including the Cys342Tyr mutation. The Fgfr2c C342Y/+ mouse model displays many of the phenotypic traits associated with Crouzon syndrome, including premature coronal suture fusion, a dome shaped neurocranium, and midfacial retrusion. This study was designed to perform a systematic evaluation of the morphological variation of the vomer in 3D micro‐computed tomography (3DμCT) scans of Fgfr2c C342Y/+ mice and their unaffected littermates. Vomer morphology was evaluated in mice at three ages: E17.5, P0, and P2. First, 3D reconstructions and slice images of 3DμCT scans were evaluated for evidence of bridging or fusion between the presphenoid bone and either the left or right vomer alae (N=81 Fgfr2cC342Y/+ mice, 92 unaffected littermates). None of the unaffected mice at any age exhibited any bridging or fusion between the vomer alae and presphenoid bone, while affected mice were increasingly likely to show bridging or fusion as age progressed. At P2, 60% of affected mice exhibited at least unilateral bridging between one of the vomer ala and the presphenoid. Second, geometric morphometric analysis was conducted on a set of 6 3D landmarks describing vomer shape, including landmarks on the vomer body and tips of the left and right alae (N=45 Fgfr2cC342Y/+ mice, 55 unaffected littermates). Mann‐Whitney U testing revealed that at each of the three ages tested, the anteroposterior lengths of the vomer bodies and vomer alae were significantly longer (p < 0.05) and the mediolateral distance between the tips of the vomer alae was also significantly increased (p < 0.001) in Fgfr2cC342Y/+ mice as compared to their unaffected littermates. The vomer is an element of the dermatocranium that interfaces with elements of the cranial base and the facial skeleton, which are components of the endocranium. This novel phenotype provides insight into the morphogenesis of the complex craniofacial traits typically associated with Crouzon syndrome and suggests the importance of evolutionary considerations in the interpretation of dysmorphogenesis associated with this FGFR2 mutation.Support or Funding InformationThis research was supported in part by NIDCR/NIH R01DE018500 R01DE022988 NICHD/NIH P01HD078233 and NSF BCS 1731909.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Characterization of the Bent Bone Dysplasia Mouse: conditional knock‐in of FGFR2M391R
Authors: Rigueur Diana , Merrill Amy 
Published: June 2021

Fibroblast Growth Factor Receptor 2 (FGFR2) regulates osteoprogenitor proliferation, self‐renewal and terminal differentiation during skeletal development, yet it remains unclear how the receptor distinctly elicits these cellular processes. We discovered a nuclear feature of FGF signaling that will elucidate with more specificity how FGFR2 regulates skeletal development. This mechanism emerged from our analysis of Bent Bone Dysplasia Syndrome (BBDS), an FGFR2‐disorder where the cell‐fate decisions of osteoprogenitor cells are biased towards self‐renewal over differentiation. We developed a mouse with a conditional knock‐in of the FGFR2 M391R mutation that causes BBDS in humans. DNA sequencing of cultured primary chondrocytes treated with Adeno‐GFP or Adeno‐Cre, confirmed efficient Cre‐mediated recombination of the knock‐in allele. Cell culture experiments and immunofluorescence further showed that the knock‐in FGFR2M391R allele functions like that of BBDS, aberrantly translocating FGFR2 to the nucleus. Moreover, generation of a Wnt1‐Cre; FGFR2M391R/+ mouse renders a phenotype, craniosynostosis, along with other defects in neural crest derived tissues, which strongly suggests that the mutation is dominant in mouse as it is in humans. Overall our preliminary data shows that the conditional knock‐in FGFR2M391R mouse can be used to model human BBDS and can also be used to parse out the unknown endogenous and pathogenic functions of nuclear FGFR2.Support or Funding InformationNIH RO1, NIH Diversity Supplement Award, and March of DimesThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Cholesterol regulates craniofacial development by modulating the WNT signaling pathway.
Authors: Gonzalez Cesar 
Published: June 2021

The cholesterol synthesis pathway produces two independent lipid molecules, cholesterol and isoprenoids, both of which have diverse cellular functions. Mutations that inhibit the cholesterol synthesis pathway result in at least 8 different human syndromes, some of which are characterized by defects in facial development. The presence of facial dysmorphia in these disorders strongly suggests that the cholesterol synthesis pathway facilitates appropriate facial development. Recently, it was demonstrated that mutation or inhibition of this pathway in zebrafish results in craniofacial abnormalities by interfering with appropriate neural crest cell differentiation. However, whether these deficits in differentiation are cholesterol independent, cholesterol dependent, or a combination of both has not been fully elucidated. In order to better understand the independent functions of cholesterol and isoprenoids during neural crest cell differentiation, we performed a combination of loss of function and pharmacological inhibition studies. Mutation of the zebrafish ortholog of hmgcs1, which encodes the first enzyme in the cholesterol synthesis pathway, disrupts the differentiation of cranial neural crest cells, but does not affect the specification and migration of these cells. Furthermore, pharmacological inhibition of each branch of the cholesterol synthesis pathway revealed a novel function for isoprenoids in neural crest differentiation. Interestingly, the cholesterol dependent mechanisms modulating cranial facial development were sonic hedgehog independent. Moreover, our preliminary analysis suggests that the inhibition of cholesterol synthesis reduces activation of the WNT signaling pathway, an essential mediator of craniofacial development. Taken together these data demonstrate a novel mechanisms by which the cholesterol synthesis pathway regulates craniofacial development.Support or Funding InformationResearch reported in this poster was supported by the National Institute Of General Medical Sciences of the National Institutes of Health under linked Award Numbers RL5GM118969, TL4GM118971, and UL1GM118970. Funding for this project was obtained from NIMH Grant no. 2G12MD007592 to the University of Texas El Paso, University of Texas El Paso Office of Research and Sponsored Projects New Investigator start‐up funding, NIGMS linked awards RL5GM118969, TL4GM118971, UL1GM118970 and the NIMH Grant no. T32MH015442 to the University of Colorado School of Medicine, Department of PsychologyThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Development, Innervation, and Involution of a Transient Cement Gland in a Giant Danio (D. cf. Malabaricus): the Role of Retinoic Acid
Authors: Nelson Hannah M. , Coffing Gabrielle , Lafontant Pascal J. 
Published: June 2021

Cement glands are transient evolutionarily adaptive adhesive organs. They mediate the attachment of a number aquatic larvae to substrates in their environments. There is significant interest in understanding the mechanisms that orchestrate their development and involution, as well as the chemical constituent of the biological adhesive they produce. We have identified and studied a cephalic and ectodermally derived cement gland in a giant danio (GD), by light microscopy, immune and lectin histochemistry. We hypothesized that early inductive embryonic events regulates the development of the gland, and that exogenous retinoic acid may disrupt its proper development. Our studies revealed that the cement gland is readily identified at hatching time, and mediates attachment of larvae until they are able to swim. At the swimming stage, the gland begins its involution and disappears by day 14. Using lectin histochemistry we demonstrate that the first differentiated goblet‐like cells that constitute the gland appear as early as 12 hours post fertilization. Using acetylated tubulin staining we also show that the gland is innervated by branches of the emerging trigeminal nerve. Lectin histochemistry also indicates that the adhesive substance within the gland is composed in part of various glycoconjugated products. Finally, treatment of GD embryos during gastrulation with exogenous retinoic acid (RA) leads to posteriorization and progressive disappearance of the gland in a dose‐dependent manner. This is the first detailed description of the development, maturation, its innervation and involution of the cement gland in a GD. Our results suggest that the cement gland is one of the earliest formed organs in the GD and that its proper development depends on maintenance of a stable RA gradient. Further studies are required for greater insights onto the function the gland.Support or Funding InformationDePauw FDC, SRF.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Impact of Selection for Facial Reduction in Dogs
Authors: Selba Molly Chisholm , Oechtering Gerhard , Heng Hock Gan , DeLeon Valerie Burke 
Published: June 2021

Through artificial selection, humans have altered the morphology of domestic dogs and produced the broad range of morphological variation seen in modern dog breeds. The purpose of this study was to analyze the effects of artificial selection for short faces in domestic dogs (Canis lupus familiaris). The morphological characteristics associated with years of selection in favor of smushed, paedomorphic faces often result in Brachycephalic Airway Syndrome (BAS), which is characterized by problems with olfaction, respiration, and thermoregulation. We used clinically obtained CT scans of dogs representing brachycephalic breeds (pugs and bulldogs), normocephalic breeds (beagles), and dogs of unknown breed. We established two groups of dogs (brachycephalic and normocephalic) based on cephalic index. In both groups, we recorded a total of 62 cranial and mandibular landmarks. Through geometric morphometric analysis, we determined that the greatest shape variation in this sample was correlated with cephalic index. The shape changes in the crania and mandibles co‐vary, and are both associated with cephalic index. Within the hard palate, the majority of the shape change associated with brachycephaly is centered on the maxilla, specifically at the carnassials. The shape change seen on the hard palate is a unique lateral displacement and rotation of the carnassials, associated with shortening of the hard palate. In contrast, the shape change seen in the mandible is mainly a uniform rostral‐caudal shortening and a medial‐lateral widening. In addition, the soft palate does not appear to be reduced in these breeds. From a functional perspective, the maxillary and mandibular carnassials become malaligned in brachycephalic dogs. The shape change seen in the carnassials demonstrates that morphological integration of the carnassial complex is disrupted in brachycephalic dogs. Despite the facial reduction observed in these breeds, the soft palate does not appear to be reduced, and these soft tissues may crowd the reduced pharyngeal space. Selection for the aesthetic traits associated with brachycephaly in domestic dog breeds results in changes to the carnassial complex and pharynx that are functionally suboptimal and might limit survival outside of a domesticated environment.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
“Evaluating the Effects of the Obturator Externus Tendon on the Posterior Femoral Neck”
Authors: Campeau Lisa M. , Schachner Emma R. , Sedlmayr Jayc C. 
Published: June 2021

The anatomical literature describes the insertion tendon of obturator externus (OE) as leaving a distinct groove on the posterior aspect of the femoral neck as it travels distally to insert in the intertrochanteric fossa, a trait proposed to be directly associated with the hyper‐extended position of the human hip. The absence of this osteological correlate from the femoral neck of chimpanzees, a sister taxon to humans and a brachiating quadruped, has resulted in the use of this trait as an indicator for the evolution of bipedalism in extinct hominins. The aim of this study was to dissect and record the path of the OE tendon and adjacent ischiofemoral ligament as well as reassess the reliability of the osteological correlate in order to determine if the groove created by the OE tendon is an acceptable indicator of the origin of bipedalism in extinct hominins. The posterior hip region of embalmed (n=27) and fresh (n=3) cadavers were dissected, and the posterior aspect of the femoral neck was cleared of periosteum to evaluate the presence or absence of the OE groove. We found that 2 cadavers had a groove consistent with the OE, and 24 did not have a groove consistent with the OE. The osteological findings varied, ranging from no bony defects, a small, medially‐placed divot near the lesser trochanter, to a variety of both horizontally and vertically positioned groves on the posterior aspect of the femoral neck. The morphology of the OE as it traveled across the posterior femoral neck also varied, ranged from predominantly muscular, a thin, mostly inferiorly‐placed tendon, to a very thick, rigid, tendinous insertion. In the specimens that demonstrated a clear indication or groove on the posterior surface of the femoral neck that could be aligned with the OE, there was no consistency in the overall morphology of that groove, the OE muscle, or its insertion tendon. Additionally, a groove parallel to the OE tendon often appeared to correlate with a thickened area in the ischiofemoral ligament. As a result, we conclude that this anatomical characteristic of the posterior femoral neck is highly variable and should not be used as an osteological correlate to indicate bipedalism in extinct hominins.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Saccadic Eye Movement and Cognition
Authors: Manuel Morganne , Tzeng Tony , Aubin Ashleigh , Devier Deidre , Canavier Carmen , Lovera Jesus 
Published: June 2021

BackgroundHorizontal saccadic eye movements (saccades) have been shown to improve performance on memory and attentional control tasks. These cognitive improvements are a result of enhanced intra‐hemispheric processing capabilities following saccades. Our goal was to determine if adding horizontal saccadic eye movements during a cognitive task would improve performance on a working memory and an attentional control, when compared to adding a control task (central eye fixation).MethodsFifty healthy, right handed students were recruited on LSUHSC–NO and UNO campuses. They attended two sessions and were randomly assigned to perform a memory or attentional control task during the first visit. The other task was then completed during the second session. In addition, they were randomized 1:1 to either saccades or central eye fixation for each session. Participants were asked to either follow a dot that changed from left and right position at 1Hz or a dot that blinked in the center of a computer screen. The memory task involved recalling a short story. The attention task involved participants responding to an arrow that appeared on the computer screen flanked by distractors. Interspersed throughout each task, participants were asked to either perform saccades or central fixation.ResultsOn the memory task, there was no group difference based on eye movements) on immediate recall (15.4±3.7), delayed recall (14.0±2.9), and 24 hour delayed recall (14.4±3.0); control group immediate recall (15.1±3.3), delayed recall (14.2±3.2), and 24 hour delayed recall (14.1±3.4), p>0.05. On the attention task, the saccades improved accuracy on incongruent flankers (97.6%±2.5) when compared to the control group (95.5%±4.0), p=0.03; but eye movements did not have an effect on accuracy for congruent flankers (99.3%±2.0) when compared to the control group (99.3%±0.8), p=0.856. Although participants performed horizontal saccadic eye movements had a faster reaction time than controls, this difference was not significance.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Comparative analysis of V1a and V1b receptor distribution in the mammalian brain
Authors: Knappe Carolin , Giesecke Torsten , Koshimizu Taka‐aki , Gimber Niclas , Schmoranzer Jan , Storm Robert , Bachmann Sebastian , Mutig Kerim 
Published: June 2021

Vasopressin (AVP) induces antidiuresis via its renal V2 receptors but also acts as a neuropeptide through activation of central V1a and V1b receptors (V1aR, V1bR). Despite a large body of functional evidence for roles of these receptors in motivated behavior, little information is available on their distribution in the brain tissue. This study was designed to provide a comparative analysis of the V1aR and V1bR distribution patterns in rodent and human brain tissues using new antisera.Antibodies to individual AVP receptors were generated and validated using respective mouse knockout tissues or overexpression of the human V1aR and V1bR in HEK293 cells. Distribution of the receptors was studied by immunofluorescence in vivo in perfused rat or mouse brains and human brain samples obtained from clinical section. Confocal microscopy or super resolution imagingwere applied for signal detection. AVP receptors expressing cell types were identified by double‐labeling for markers of neurons (CTIP2 or SATB2) or glial cells (GFAP).Application of the anti‐V1aR antibody on rat or mouse brain sections produced signal in pyramidal cells of the isocortical layers II and V, astrocytes, neurons of the medial habenula, the suprachiasmatic and supraoptic hypothalamic nuclei, as well as in the CA2 and CA3 fields of hippocampus, whereas no significant signal was detected in the choroid plexus. V1bR signal was present in pyramidal cells of the isocortical layers II and V, neurons of the medial and lateral habenula, the suprachiasmatic and supraopticus nuclei of hypothalamus and in basolateral cellular aspects of the choroid epithelia. Evaluation of human brain samples revealed similar V1aR and V1bR distribution patterns, as compared to rodents.In summary, our results document the distribution patterns of V1aR and V1bR in the rodent brain, thus corroborating previous functional data on the role of AVP in motivated behavior.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.