Mitochondrial Porins in Mammals: Insights into Functional Roles from Mutant Mice and Cells

Knocking-out the human face genes TBX15 and PAX1 in mice alters facial and other physical morphology

10.1101/2021.05.26.445773 ◽

2021 ◽

Author(s):

Yu Qian ◽

ziyi Xiong ◽

Yi Li ◽

haibo Zhou ◽

Manfred Kayser ◽

...

Keyword(s):

Association Studies ◽

Three Dimensional ◽

Mutant Mice ◽

Genome Wide Association Studies ◽

Facial Morphology ◽

Morphological Alterations ◽

Functional Roles ◽

Adult Mice ◽

Phenotype Analysis ◽

The Face

DNA variants in or closed to the human TBX15 and PAX1 genes have been repeatedly associated with facial morphology in independent genome-wide association studies, while their functional roles in determining facial morphology remains to be understood. We generated Tbx15 knockout ( Tbx15 -/- ) and Pax1 knockout ( Pax1 -/- ) mice by applying the one-step CRISPR/Cas9 method. A total of 75 adult mice were used for subsequent phenotype analysis, including 38 Tbx15 mice (10 homozygous Tbx15 -/- , 18 heterozygous Tbx15 +/- , 10 wild-type WT) and 37 Pax1 mice (12 homozygous Pax1 -/- , 15 heterozygous Pax1 +/- , 10 WT mice). Facial and other physical morphological phenotypes were obtained from three-dimensional (3D) images acquired with the HandySCAN BLACK scanner. Compared to WT mice, the Tbx15 -/- mutant mice had significantly shorter faces ( P =1.08E-8, R2=0.61) and their ears were in a significantly lower position ( P =3.54E-8, R2=0.62) manifesting an “ear dropping” characteristic. Besides these face alternations, Tbx15 -/- mutant mice displayed significantly lower weight as well as shorter body and limb length. Pax1 -/- mutant mice showed significantly longer noses ( P =1.14E-5, R2=0.46) relative to WT mice, but otherwise displayed less obvious morphological alterations than Tbx15 -/- mutant mice did. Because the Tbx15 and Pax1 effects on facial morphology we revealed here in mice are largely consistent with previously reported TBX15 and PAX1 face associations in humans, we suggest that the functional role these two genes play on determining the face of mice is similar to the functional impact their human homologues have on the face of humans.

Download Full-text

An N-terminally truncated Smad2 protein can partially compensate for loss of full-length Smad2

Biochemical Journal ◽

10.1042/bj20080014 ◽

2008 ◽

Vol 417 (1) ◽

pp. 205-212 ◽

Cited By ~ 1

Author(s):

Debipriya Das ◽

Rebecca A. Randall ◽

Caroline S. Hill

Keyword(s):

Transcriptional Activation ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Full Length ◽

Mutant Mice ◽

Embryonic Fibroblasts ◽

Functional Roles ◽

Internal Initiation ◽

Deficient Mice ◽

Tgfβ Superfamily

TGFβ (transforming growth factor β) superfamily signalling is critical both for early embryonic development and later for tissue homoeostasis in adult organisms. The use of gene-disruption techniques in mice has been essential to understanding the functional roles of the components of the pathways downstream of TGFβ superfamily ligands, in particular, the receptors and the Smads that transduce signals from the plasma membrane to the nucleus. Smad2 functions downstream of TGFβ, Activin and Nodal, and a number of Smad2 mutant mice have been generated by different laboratories. Although in all cases these Smad2-deficient mice were embryonic lethal, those created by deletion of the first coding exon survived longer than those generated by replacing part of the MH (Mad homology) 1 domain or deleting all or part of the MH2 domain. Moreover, they displayed a less severe phenotype, as they were capable of transiently inducing mesoderm. In the present study, we show that embryonic fibroblasts taken from the Smad2 mutant mice created by deletion of the first coding exon express a small amount of an N-terminally truncated Smad2 protein. We show this protein results from internal initiation at Met241 and encodes the entire MH2 domain and the C-terminal part of the linker. We demonstrate that this protein is incorporated into Smad heteromeric complexes, can interact with DNA-binding transcription factors and thereby can mediate TGFβ-induced transcriptional activation from a number of TGFβ-responsive elements. We propose that this functional truncated Smad2 protein can partially compensate for the loss of full-length Smad2, thereby providing an explanation for the differing phenotypes of Smad2 mutant mice.

Download Full-text

The Iroquois Homeobox Gene Irx2 Is Not Essential for Normal Development of the Heart and Midbrain-Hindbrain Boundary in Mice

Molecular and Cellular Biology ◽

10.1128/mcb.23.22.8216-8225.2003 ◽

2003 ◽

Vol 23 (22) ◽

pp. 8216-8225 ◽

Cited By ~ 36

Author(s):

Mélanie Lebel ◽

Pooja Agarwal ◽

Chi Wa Cheng ◽

M. Golam Kabir ◽

Toby Y. Chan ◽

...

Keyword(s):

Heart Development ◽

Homeobox Gene ◽

Mutant Mice ◽

Phenotypic Analysis ◽

Functional Roles ◽

Developing Heart ◽

Dynamic Expression ◽

Evolutionarily Conserved ◽

And Function ◽

Deficient Mice

ABSTRACT The Iroquois homeobox (Irx) genes have been implicated in the specification and patterning of several organs in Drosophila and several vertebrate species. Misexpression studies of chick, Xenopus, and zebra fish embryos have demonstrated that Irx genes are involved in the specification of the midbrain-hindbrain boundary. All six murine Irx genes are expressed in the developing heart, suggesting that they might possess distinct functions during heart development, and a role for Irx4 in normal heart development has been recently demonstrated by gene-targeting experiments. Here we describe the generation and phenotypic analysis of an Irx2-deficient mouse strain. By targeted insertion of a lacZ reporter gene into the Irx2 locus, we show that lacZ expression reproduces most of the endogenous Irx2 expression pattern. Despite the dynamic expression of Irx2 in the developing heart, nervous system, and other organs, Irx2-deficient mice are viable, are fertile, and appear to be normal. Although chick Irx2 has been implicated in the development of the midbrain-hindbrain region, we show that Irx2-deficient mice develop a normal midbrain-hindbrain boundary. Furthermore, Irx2-deficient mice have normal cardiac morphology and function. Functional compensation by other Irx genes might account for the absence of a phenotype in Irx2-deficient mice. Further studies of mutant mice of other Irx genes as well as compound mutant mice will be necessary to uncover the functional roles of these evolutionarily conserved transcriptional regulators in development and disease.

Download Full-text

New insights into heparan sulphate biosynthesis from the study of mutant mice

Biochemical Society Symposium ◽

10.1042/bss0690047 ◽

2002 ◽

Vol 69 ◽

pp. 47-57 ◽

Cited By ~ 8

Author(s):

Catherine L. R. Merry ◽

John T. Gallagher

Keyword(s):

Growth Factors ◽

Biosynthetic Pathway ◽

Heparan Sulphate ◽

Mutant Mice ◽

Gene Products ◽

Multiple Gene ◽

Adhesion Proteins ◽

Ligand Interactions

Heparan sulphate (HS) is an essential co-receptor for a number of growth factors, morphogens and adhesion proteins. The biosynthetic modifications involved in the generation of a mature HS chain may determine the strength and outcome of HS–ligand interactions. These modifications are catalysed by a complex family of enzymes, some of which occur as multiple gene products. Various mutant mice have now been generated, which lack the function of isolated components of the HS biosynthetic pathway. In this discussion, we outline the key findings of these studies, and use them to put into context our own work concerning the structure of the HS generated by the Hs2st-/- mice.

Download Full-text