Heart and extra-embryonic mesodermal defects in mouse embryos lacking the bHLH transcription factor Hand1

Firulli, Anthony B.; McFadden, David G.; Lin, Qing; Srivastava, Deepak; Olson, Eric N.

doi:10.1038/ng0398-266

Cited by 345 publications

(314 citation statements)

References 15 publications

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“…Hand1 expression within NCC-derived mesenchyme of the distal PAs is first detectable at E9.5. Expression cannot be detected at E9.0 using the sensitive Hand1 lacZ knock-in allele (Firulli et al, 1998;Fig. 1B-E).…”

Section: Hand1 Phospho-mutant Expression Within the Pas Results In Prmentioning

confidence: 99%

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Hand1 phosphoregulation within the distal arch neural crest is essential for craniofacial morphogenesis

et al. 2014

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In this study we examine the consequences of altering Hand1 phosphoregulation in the developing neural crest cells (NCCs) of mice. Whereas Hand1 deletion in NCCs reveals a nonessential role for Hand1 in craniofacial development and embryonic survival, altering Hand1 phosphoregulation, and consequently Hand1 dimerization affinities, in NCCs results in severe mid-facial clefting and neonatal death. Hand1 phosphorylation mutants exhibit a noncell-autonomous increase in pharyngeal arch cell death accompanied by alterations in Fgf8 and Shh pathway expression. Together, our data indicate that the extreme distal pharyngeal arch expression domain of Hand1 defines a novel bHLH-dependent activity, and that disruption of established Hand1 dimer phosphoregulation within this domain disrupts normal craniofacial patterning.

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Section: Hand1 Phospho-mutant Expression Within the Pas Results In Prmentioning

confidence: 99%

“…1; Firulli et al, 1998;Ruest et al, 2004). As the Hand1 PO4− and Hand1 PO4+ mutants are knock-in alleles, these Hand1 dimer mutants are expressed at endogenous levels in a spatio-temporal pattern consistent with wild-type Hand1.…”

Section: Discussionmentioning

confidence: 99%

Hand1 phosphoregulation within the distal arch neural crest is essential for craniofacial morphogenesis

et al. 2014

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“…Taken together these data indicate that Tbx5 is involved in an initial regulatory network displaying mutual regulation with Nkx2.5 (Sun et al, 2004) and supports with Mef2c the induction of downstream factors of terminal differentiation . In addition, MLC1a, an atrial marker gene, is up-regulated upon Tbx5 overexpression, while Hand1, a transcription factor that is expressed in the left ventricle and prevents terminal differentiation (Firulli et al, 1998), is down-regulated. The latter one is in agreement with the fact that Tbx5 favours terminal differentiation as discussed before.…”

Section: Discussionmentioning

confidence: 99%

“…5). Unexpected, the expression of Hand1, a factor expressed in the left ventricle (Firulli et al, 1998), was also down-regulated from day 10 onward in Tbx5-overexpressing cells compared with wild-type cells (Fig. 4).…”

Section: Differentiating Tbx5mentioning

confidence: 90%

Tbx5 overexpression favors a first heart field lineage in murine embryonic stem cells and in Xenopus laevis embryos

Herrmann

Bundschu

Kühl

et al. 2011

Developmental Dynamics

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The T-box transcription factor Tbx5 is involved in several developmental processes including cardiogenesis. Early steps of cardiac development are characterised by the formation of two cardiogenic lineages, the first (FHF) and the second heart field (SHF) lineage, which arise from a common cardiac progenitor cell population. To further investigate the function of Tbx5 during cardiogenesis, we generated a murine embryonic stem cell line constitutively overexpressing Tbx5. Differentiation of these cells is characterised by an earlier and increased appearance of contracting cardiomyocytes that beat with a higher frequency than control cells. In semi-quantitative and quantitative RT-PCR analyses, we observed an up-regulation of cardiac marker genes such as Troponin T, endogenous Tbx5, and Nkx2.5 and a down-regulation of others like BMP4 and Hand2. Similar data were gained in Xenopus laevis arguing for a conserved function of Tbx5. Furthermore, markers of the conduction system and atrial cardiomyocytes were increased.

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“…Mice express two duplicates of Hand. Among other defects, loss-of-function mutants in Hand1 are defective in left ventricle formation, whereas loss of function mutants in Hand2 fail to form the right ventricle [73][74][75][76] . The functions of two duplicates have become partitioned such that each is associated with formation of a morphological partition of an organ.…”

Section: Heart Evolutionmentioning

confidence: 99%

Gene duplications, robustness and evolutionary innovations

Wagner

2008

BioEssays

113

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Gene duplications, robustness and evolutionary innovations Gene duplications, robustness and evolutionary innovations AbstractMutational robustness facilitates evolutionary innovations. Gene duplications are unique kinds of mutations, in that they generally increase such robustness. The frequent association of gene duplications in regulatory networks with evolutionary innovation is thus a special case of a general mechanism linking innovation to robustness. The potential power of this mechanism to promote evolutionary innovations on large time scales is illustrated here with several examples. These include the role of gene duplications in the vertebrate radiation, flowering plant evolution and heart development, which encompass some of the most striking innovations in the evolution of life. Gene duplications, robustness, and evolutionary innovationsAndreas Wagner AbstractMutational robustness facilitates evolutionary innovations in biological systems. Gene duplications are unique kinds of mutations, in that they generally increase such robustness. The frequent association of gene duplications in regulatory networks with evolutionary innovation thus exemplifies a general mechanism linking innovation to robustness. I illustrate the potential power of this mechanism on large time scales with the role of gene duplications in the vertebrate radiation, flowering plant evolution, and heart development, which encompass some of the most striking innovations in the evolution of life. Mutational robustnessMutational robustness is a biological's system ability to withstand mutations. Such robustness exists on multiple levels of biological organization. A case in point are random mutagenesis experiments of various proteins. They suggest that only a small fraction of mutations affect protein function adversely. For instance, a study of the bacteriophage T4 lysozyme generated more than 2000 random amino acid changes in the protein. Only 16% of them affected lysozyme function 1 . Other examples come from regulatory gene networks, such as the molecular network specifying fruit fly segments. Such networks may tolerate much quantitative variation in interactions among network genes 2-5 . Examples at the highest level of organization include macroscopic traits. Even substantial genetic variation -ultimately caused by mutations -may leave such traits unchanged. Take the vulva of the nematode worms Caenorhabditis elegans and Pristionchus pacificus 6 . These organisms shared a common ancestor 200-300 million years ago. Their vulvae are very similar, yet the genetic and cellular networks producing them have diverged greatly. For example, whereas in C. elegans one specific cell -the anchor cell -induces vulva development, multiple gonadal cells are responsible for this induction in P. pacificus 7 . Similarly, the same key signaling molecules, such as Wnt, may play a positive role in the network for vulval induction in C. elegans, but a negative role in P. pacificus 8,9 . In sum, mutational robustness is everywhere, from proteins to or...

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Heart and extra-embryonic mesodermal defects in mouse embryos lacking the bHLH transcription factor Hand1

Cited by 345 publications

References 15 publications

Hand1 phosphoregulation within the distal arch neural crest is essential for craniofacial morphogenesis

Hand1 phosphoregulation within the distal arch neural crest is essential for craniofacial morphogenesis

Tbx5 overexpression favors a first heart field lineage in murine embryonic stem cells and in Xenopus laevis embryos

Gene duplications, robustness and evolutionary innovations

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