A two-locus model for experience-conditioned direction of paw usage in the mouse is suggested by dominant and recessive constitutive paw usage behaviours

Genome ◽  
2001 ◽  
Vol 44 (5) ◽  
pp. 872-882 ◽  
Author(s):  
Fred G Biddle ◽  
Danielle A Jones ◽  
Brenda A Eales
Keyword(s):  
Test Chamber ◽  
Functional Difference ◽  
Constitutive Behaviour ◽  
Loss Of Function ◽  
Phenotypic Analysis ◽  
Locus Heterogeneity ◽  
Locus Model ◽  
Left Right Asymmetry ◽  
Conditioned Behaviour ◽  
Behaviour Learning

Left-right direction of paw usage in the mouse depends on the genotype and the directional nature of the test. There are two phenotypic classes; in some strains, direction of paw usage is learned or conditioned by the direction of the initial test chamber and the experience of reaching and, in other strains, paw usage is a constitutive behaviour not affected by previous experience. We report the evidence for locus heterogeneity in the cause of constitutive versus experience-conditioned paw usage from a phenotypic analysis of F1 hybrid generations from the experience-conditioned C57BL/6J, C3H/HeHa, and SWV strains and the constitutive CDS/Lay and DBA/2J strains. The F1 hybrids between strains of different phenotypic classes provide evidence of locus heterogeneity. Constitutive paw usage in CDS/Lay is phenotypically dominant to experience-conditioned behaviour in both C57BL/6J and SWV. However, constitutive paw usage in DBA/2J is phenotypically recessive to experience-conditioned behaviour in C57BL/6J and dominant to experience-conditioned behaviour in SWV. Among the experience-conditioned strains, C57BL/6J is highly lateralized but SWV is only weakly lateralized. Our data suggest a model in which C57BL/6J may have a "strong" allele that identifies a functional difference between the constitutive paw usage of CDS/Lay and DBA/2J. DBA/2J may have a loss-of-function mutation at the same locus that is recessive to the strong C57BL/6J allele. SWV may have a "weak" allele and the (SWV × D2)F1 compound heterozygote may be below a threshold for detectability of experience-conditioned behaviour, making the constitutive behaviour of DBA/2J appear to be dominant to the experience-conditioned behaviour of SWV. CDS/Lay may have a dominant allele at a second locus that suppresses experience-conditioned behaviour in all F1 hybrids.Key words: mouse, left-right asymmetry of hand usage, behavioural genetics, experience-conditioned behaviour, dominant and recessive constitutive behaviour, learning, memory.

Mouse genetic model for left-right hand usage: Context, direction, norms of reaction, and memory

Genome ◽  
1999 ◽  
Vol 42 (6) ◽  
pp. 1150-1166 ◽  
Author(s):  
Fred G Biddle ◽  
Brenda A Eales
Keyword(s):  
Genetic Model ◽  
Quantitative Difference ◽  
Laboratory Mouse ◽  
Qualitative Difference ◽  
Test Chamber ◽  
Inbred Strains ◽  
The Difference ◽  
Left Right Asymmetry ◽  
Conditioned Behaviour ◽  
The Right

Asymmetry of paw usage in the laboratory mouse is an experimental model for left-right asymmetry of hand usage. Given a set number of reaches into a centrally placed food tube (an unbiased or U-world test), individual mice exhibit a number of left and right paw reaches that is reliably expressed on retesting. Whereas different inbred strains appear to have equal numbers of individual mice with a left- or a right-preferred paw after a U-world test, there are significant differences among strains in the degree or strength of lateralization of the preferred paw. We report here a systematic series of tests of paw usage with naive mice and retests of the individuals in test chambers with the food tube biased to the left or to the right, contrasting the highly lateralized C57BL/6J and the very weakly lateralized (or ambilateral) CDS/Lay inbred strains and their (B6 × CDS) F1 generation. The results caused a shift in the paradigm of paw usage. There is an unexpected qualitative difference in paw usage between C57BL/6J and CDS/Lay. C57BL/6J is random in its left-right paw usage, but it is conditioned by the left or right direction of the initial biased-world test and by usage. CDS/Lay is constitutively equal-pawed, responds very little to direction of the test chamber, and is not conditioned by it. The probability of left-paw versus right-paw usage depends on both the genotype and the context of the test. The (B6 × CDS) F1 generation suggests that constitutive equal-paw usage of CDS/Lay is dominant to experience-conditioned paw usage of C57BL/6J. There is also an apparent quantitative difference between the very weakly lateralized (ambilateral) preferred paw usage in CDS/Lay and the highly lateralized preferred paw usage in C57BL/6J. The difference in degree of lateralization of preferred paw usage between the constitutively equal-pawed CDS/Lay strain and (B6 × CDS) F1 generation must originate from allelic differences at other gene loci between the CDS/Lay and C57BL/6J parental strains. The SWV and NOD/Lt strains were also assessed in asymmetrical tests because they were known to be weakly lateralized and similar to each other in a U-world test and to be significantly different from both C57BL/6J and CDS/Lay. SWV is experience-conditioned and weakly lateralized; NOD/Lt is constitutively equal-pawed and weakly lateralized. Further analysis will determine the genetic cause of the qualitative difference between constitutive equal-paw and experience-conditioned paw usage and the genetic cause of the quantitative differences in degree of lateralization of the preferred paw within each type of paw usage.Key words: mouse, left-right handedness, behavioural genetics, phenotypic reaction norms, constitutive behaviour, experience-conditioned behaviour, memory.

scholarly journals GAGA Factor Isoforms Have Distinct but Overlapping Functions In Vivo

2001 ◽  
Vol 21 (24) ◽  
pp. 8565-8574 ◽  
Author(s):  
Anthony J. Greenberg ◽  
Paul Schedl
Keyword(s):  
Fusion Protein ◽  
Transcriptional Activation ◽  
Functional Difference ◽  
Wild Type ◽  
Gaga Factor ◽  
Phenotypic Analysis ◽  
Alternatively Spliced

ABSTRACT The Drosophila melanogaster GAGA factor (encoded by the Trithorax-like [Trl] gene) is required for correct chromatin architecture at diverse chromosomal sites. The Trl gene encodes two alternatively spliced isoforms of the GAGA factor (GAGA-519 and GAGA-581) that are identical except for the length and sequence of the C-terminal glutamine-rich (Q) domain. In vitro and tissue culture experiments failed to find any functional difference between the two isoforms. We made a set of transgenes that constitutively express cDNAs coding for either of the isoforms with the goal of elucidating their roles in vivo. Phenotypic analysis of the transgenes in Trl mutant background led us to the conclusion that GAGA-519 and GAGA-581 perform different, albeit largely overlapping, functions. We also expressed a fusion protein with LacZ disrupting the Q domain of GAGA-519. This LacZ fusion protein compensated for the loss of wild-type GAGA factor to a surprisingly large extent. This suggests that the Q domain either is not required for the essential functions performed by the GAGA protein or is exclusively used for tetramer formation. These results are inconsistent with a major role of the Q domain in chromatin remodeling or transcriptional activation. We also found that GAGA-LacZ was able to associate with sites not normally occupied by the GAGA factor, pointing to a role of the Q domain in binding site choice in vivo.

16. Physiological effects of IDH1 loss-of-function on Chondrocyte Differentiation through Hedgehog Pathway upregulation

2018 ◽  
Author(s):  
Cassie Tyson
Keyword(s):  
Developmental Stages ◽  
Hedgehog Pathway ◽  
Chondrocyte Differentiation ◽  
Loss Of Function ◽  
Wild Type ◽  
Phenotypic Analysis ◽  
Growth Plate Chondrocytes ◽  
Idh Mutations ◽  
Cartilage Tumors ◽  
Deficient Mice

Cartilage tumors are the most common and terminal primary neoplasms in bone. Physiologically, bones formed through endochondral ossification are regulated by the Hedgehog pathway and Parathyroid hormone-like hormone feedback loop. The upregulation of the infamous Hedgehog pathway has been demonstrated in several non-cartilaginous neoplasms. Recently, frequent mutational events of isocitrate dehydrogenase1 (IDH1) were identified in cartilage tumors. In other neoplasms, IDH mutations produces an oncometabolite that can promote HIF1a activation, contributing to tumorigenesis. Currently, the role of IDH1 mutations in cartilage tumors remain unknown. Investigating the physiological aspect of IDH1proves useful in identifying novel therapeutic targets for cartilage tumors. IDH1 deficient and wild-type littermates, were harvested for forelimbs and hindlimbs at various developmental stages for phenotypic analysis via hematoxylin and eosin staining. Histological analysis demonstrated IDH1 homozygous deficient mice at embryonic stages exhibited dwarfism and an elongated layer of hypertrophic chondrocytes. This was verified via immunohistochemistry Type 10 Collagen staining and Quantitative PCR (qPCR) using the chondrocyte terminal differentiation marker Col10a1. Whole skeletons of IDH1 deficient mice were subjected to skeletal double staining which demonstrated delayed mineralization of underdeveloped IDH1 deficient mice contrasted with wild-type littermates. qPCR was performed to examine the status of chondrocyte differentiation through the Hedgehog pathway in cultured primarymouse growth plate chondrocytes. Interestingly, IDH1 deficient non-neoplastic cells revealed significant upregulation of Hedgehog target molecules in IDH1 deficient chondrocytes. As a result, the loss-offunction of IDH1 was identified as a potential impairment of chondrocyte differentiation and a factor towards chondrocyte tumorgenisis.

scholarly journals De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis

2017 ◽  
Vol 114 (35) ◽  
pp. E7341-E7347 ◽  
Author(s):  
Andrew T. Timberlake ◽  
Charuta G. Furey ◽  
Jungmin Choi ◽  
Carol Nelson-Williams ◽  
Erin Loring ◽  
...  
Keyword(s):  
De Novo ◽  
Erk Signaling ◽  
Loss Of Function ◽  
De Novo Mutations ◽  
Neurodevelopmental Outcomes ◽  
Locus Heterogeneity ◽  
Syndromic Craniosynostosis ◽  
New Genes ◽  
Morphogenetic Protein ◽  
Nuclear Targets

Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent–offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10.9-fold enrichment, P = 2.4 × 10−11). SMAD6 had 4 de novo and 14 transmitted mutations; no other gene had more than 1. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease. Collectively, these mutations contribute to 10% of probands. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mechanism. A common risk variant near BMP2 increased the penetrance of SMAD6 mutations and was overtransmitted to patients with de novo mutations in other genes in these pathways, supporting a frequent two-locus pathogenesis. These findings implicate new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes. Finally, the use of pathways identified in rare syndromic disease to find genes accounting for non-syndromic cases may prove broadly relevant to understanding other congenital disorders featuring high locus heterogeneity.

scholarly journals AHK3-Mediated Cytokinin Signaling Is Required for the Delayed Leaf Senescence Induced by SSPP

2019 ◽  
Vol 20 (8) ◽  
pp. 2043
Author(s):  
Yanan Wang ◽  
Xiyu Zhang ◽  
Yanjiao Cui ◽  
Lei Li ◽  
Dan Wang ◽  
...  
Keyword(s):  
Leaf Senescence ◽  
Protein Phosphatase ◽  
Developmental Process ◽  
Loss Of Function ◽  
Cytokinin Signaling ◽  
Phenotypic Analysis ◽  
Exogenous Cytokinin ◽  
Cytokinin Treatment ◽  
Encoding Gene ◽  
Multiple Signaling

Leaf senescence is a highly-programmed developmental process regulated by an array of multiple signaling pathways. Our group previously reported that overexpression of the protein phosphatase-encoding gene SSPP led to delayed leaf senescence and significantly enhanced cytokinin responses. However, it is still unclear how the delayed leaf senescence phenotype is associated with the enhanced cytokinin responses. In this study, we introduced a cytokinin receptor AHK3 knockout into the 35S:SSPP background. The phenotypic analysis of double mutant revealed that AHK3 loss-of-function reversed the delayed leaf senescence induced by SSPP. Moreover, we found the hypersensitivity of 35S:SSPP to exogenous cytokinin treatment disappeared due to the introduction of AHK3 knockout. Collectively, our results demonstrated that AHK3-mediated cytokinin signaling is required for the delayed leaf senescence caused by SSPP overexpression and the detailed mechanism remains to be further elucidated.

scholarly journals Localization and loss-of-function implicates ciliary proteins in early, cytoplasmic roles in left-right asymmetry

2005 ◽  
Vol 234 (1) ◽  
pp. 176-189 ◽  
Author(s):  
Dayong Qiu ◽  
Shing-Ming Cheng ◽  
Laryssa Wozniak ◽  
Megan McSweeney ◽  
Emily Perrone ◽  
...  
Keyword(s):  
Loss Of Function ◽  
Left Right Asymmetry

scholarly journals Prominins control ciliary length throughout the animal kingdom: New lessons from human prominin-1 and zebrafish prominin-3

2020 ◽  
Vol 295 (18) ◽  
pp. 6007-6022 ◽  
Author(s):  
József Jászai ◽  
Kristina Thamm ◽  
Jana Karbanová ◽  
Peggy Janich ◽  
Christine A. Fargeas ◽  
...  
Keyword(s):  
Primary Cilia ◽  
Photoreceptor Cells ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Loss Of Function ◽  
Animal Kingdom ◽  
Left Right Asymmetry ◽  
And Function ◽  
The Impact

Prominins (proms) are transmembrane glycoproteins conserved throughout the animal kingdom. They are associated with plasma membrane protrusions, such as primary cilia, as well as extracellular vesicles derived thereof. Primary cilia host numerous signaling pathways affected in diseases known as ciliopathies. Human PROM1 (CD133) is detected in both somatic and cancer stem cells and is also expressed in terminally differentiated epithelial and photoreceptor cells. Genetic mutations in the PROM1 gene result in retinal degeneration by impairing the proper formation of the outer segment of photoreceptors, a modified cilium. Here, we investigated the impact of proms on two distinct examples of ciliogenesis. First, we demonstrate that the overexpression of a dominant-negative mutant variant of human PROM1 (i.e. mutation Y819F/Y828F) significantly decreases ciliary length in Madin–Darby canine kidney cells. These results contrast strongly to the previously observed enhancing effect of WT PROM1 on ciliary length. Mechanistically, the mutation impeded the interaction of PROM1 with ADP-ribosylation factor–like protein 13B, a key regulator of ciliary length. Second, we observed that in vivo knockdown of prom3 in zebrafish alters the number and length of monocilia in the Kupffer's vesicle, resulting in molecular and anatomical defects in the left-right asymmetry. These distinct loss-of-function approaches in two biological systems reveal that prom proteins are critical for the integrity and function of cilia. Our data provide new insights into ciliogenesis and might be of particular interest for investigations of the etiologies of ciliopathies.

scholarly journals Molecular and Phenotypic Analysis of 25 Recessive, Homozygous-Viable Alleles at the Mouse agouti Locus

Genetics ◽  
2002 ◽  
Vol 160 (2) ◽  
pp. 659-674
Author(s):  
Rosalynn J Miltenberger ◽  
Kazumasa Wakamatsu ◽  
Shosuke Ito ◽  
Richard P Woychik ◽  
Liane B Russell ◽  
...  
Keyword(s):  
Loss Of Function ◽  
Wild Type ◽  
Allelic Series ◽  
Phenotypic Analysis ◽  
Protein Coding ◽  
Agouti Locus ◽  
Expression Control ◽  
Gene Expression Control ◽  
Specific Locus

Abstract Agouti is a paracrine-acting, transient antagonist of melanocortin 1 receptors that specifies the subapical band of yellow on otherwise black hairs of the wild-type coat. To better understand both agouti structure/function and the germline damage caused by chemicals and radiation, an allelic series of 25 recessive, homozygous-viable agouti mutations generated in specific-locus tests were characterized. Visual inspection of fur, augmented by quantifiable chemical analysis of hair melanins, suggested four phenotypic categories (mild, moderate, umbrous-like, severe) for the 18 hypomorphs and a single category for the 7 amorphs (null). Molecular analysis indicated protein-coding alterations in 8 hypomorphs and 6 amorphs, with mild-moderate phenotypes correlating with signal peptide or basic domain mutations, and more devastating phenotypes resulting from C-terminal lesions. Ten hypomorphs and one null demonstrated wild-type coding potential, suggesting that they contain mutations elsewhere in the ≥125-kb agouti locus that either reduce the level or alter the temporal/spatial distribution of agouti transcripts. Beyond the notable contributions to the field of mouse germ cell mutagenesis, analysis of this allelic series illustrates that complete abrogation of agouti function in vivo occurs most often through protein-coding lesions, whereas partial loss of function occurs slightly more frequently at the level of gene expression control.

Sign in / Sign up

Export Citation Format

Share Document