Multicellular development requires the precise management of cellular behaviors including proliferation, migration, and differentiation. These are coordinated through intercellular communication pathways, such as growth factor signaling, that couple extracellular information with internal effectors, including transcription factors (TFs) (Fantauzzo and Soriano, 2015; Lemmon and Schlessinger, 2010). The balance between opposing transcription programs is tuned by signaling pathways which activate specific TFs or in some cases cofactors that direct the behavior of a common TF. One example of the latter is the essential transcription factor Serum Response Factor (SRF) (Posern and Treisman, 2006). SRF is necessary for the expression of immediate early genes (IEGs) in cells stimulated with serum or growth factors, as well as many genes related to the actin cytoskeleton, contractility, and muscle differentiation.

SRF binds a conserved DNA regulatory sequence known as a CArG box, a motif found at many cytoskeletal and growth-factor inducible gene promoters (Mohun et al., 1991; Norman et al., 1988; Sun et al., 2006b). SRF can, however, effect at least two unique transcriptional programs by coupling with two families of cofactors that compete for a common binding site on SRF itself (Miano, 2003; Wang et al., 2004 Figure 1A). The ternary complex factors (TCFs) are E26 transformation-specific (ETS) family proteins activated by extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation (Mylona et al., 2016). Once activated, they bind DNA and promote cellular proliferation by transcribing IEGs in coordination with SRF (Esnault et al., 2017; Gualdrini et al., 2016). There are three TCF members in mouse and human: ELK1, ELK3/NET, and ELK4/SAP1 (Posern and Treisman, 2006). Opposing SRF-TCF activity are the Myocardin Related Transcription Factors (MRTFs). These cofactors rely on SRF to bind DNA, promote cytoskeletal gene expression, and are particularly important in muscle differentiation (Posern and Treisman, 2006). MRTFs bind to and are inhibited by G-actin. Polymerization of G-actin into F-actin liberates MRTFs to translocate to the nucleus and bind SRF (Miralles et al., 2003). This can be promoted by multiple signaling pathways, including phosphoinositide 3-kinase (PI3K), that stimulate guanine nucleotide exchange factors to activate F-actin-promoting Rho-family GTPases (Brachmann et al., 2005; Hanna and El-Sibai, 2013; Jiménez et al., 2000; Vasudevan and Soriano, 2014). MRTFs are also positively and negatively regulated by extensive phosphorylation (Panayiotou et al., 2016). Three MRTFs are known to interact with SRF: Myocardin itself, MRTF-A/MKL1/MAL, and MRTF-B (Parmacek, 2007). Myocd is expressed specifically in muscle while Mrtfa and Mrtfb are more broadly expressed (Posern and Treisman, 2006). A fourth MRTF, MAMSTR/MASTR, interacts with MEF2 proteins and is not known to bind SRF (Creemers et al., 2006).

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Srf and its cofactors have been extensively studied genetically. Srf^-/- mutant mice die between E6.5 and E8.5 showing defects in mesoderm formation (Arsenian et al., 1998; Niu et al., 2005). Cofactor knockouts are comparatively mild. Single TCF mutants are all fully or partially viable (Ayadi et al., 2001; Cesari et al., 2004; Costello et al., 2004; Weinl et al., 2014) and Elk1; Elk3; Elk4 triple null embryos have not been described in detail but survive until E14.5 without obvious defects (Costello et al., 2010; Gualdrini et al., 2016). Mrtfa^-/- mutant mice are viable (Li et al., 2006; Sun et al., 2006a) whereas Mrtfb^-/- mice are inviable between E13.5-E15.5, exhibiting cardiovascular defects (Li et al., 2012; Oh et al., 2005). Myocd^-/- mice have the most severe phenotype and die at E10.5, also from cardiovascular defects (Espinoza-Lewis and Wang, 2014; Li et al., 2003). Mrtfa; Mrtfb double null mice have not been described, but conditional double mutants have shown these factors exhibit redundancy and broadly phenocopy loss of Srf in several tissues and cell types (Cenik et al., 2016; Guo et al., 2018; Li et al., 2005a; Trembley et al., 2015). However, studies comparing Srf and Mrtfa; Mrtfb mutants are not always identical. In megakaryocytes, loss of Mrtfa and Mrtfb is more severe than loss of Srf and there are large gene expression differences in the two models (Smith et al., 2012; Halene et al., 2010). Indeed, there is evidence that MRTFs may regulate genes independent of SRF or act as cofactors for TFs other than SRF (Asparuhova et al., 2011; Kim et al., 2017). Whether the differences in Srf versus Mrtfa; Mrtfb loss-of-function studies are due to SRF-TCF activity, SRF-independent MRTF activity, or TCF/MRTF-independent SRF activity remains uncertain. These studies are summarized in Supplementary file 1.

One tissue in which SRF was found to be essential is the neural crest (NC) (Newbern et al., 2008; Vasudevan and Soriano, 2014). The NC is a transient developmental population of cells that arises from the dorsal neural tube, migrates ventrally throughout the embryo, and gives rise to numerous cell types including the bone and connective tissue of the face, as well as smooth muscle cells in the cardiac outflow tract (Bronner and Simões-Costa, 2016). The extensive migration, proliferation, and various differentiation outcomes these cells undergo requires accurate coordination, and decades of study have revealed a panoply of signaling pathways and transcription factors important in these processes, including the fibroblast growth factor (FGF) pathway, platelet-derived growth factor (PDGF) pathway, and SRF itself (Brewer et al., 2015; Dinsmore and Soriano, 2018; Newbern et al., 2008; Rogers and Nie, 2018; Tallquist and Soriano, 2003; Vasudevan and Soriano, 2014). We and others have previously shown that Srf is required in the NC for craniofacial and cardiovascular development (Newbern et al., 2008; Vasudevan and Soriano, 2014). Intriguingly, mice homozygous for a hypomorphic allele of Mrtfb die shortly after birth with cardiac outflow tract defects and can be rescued by a neural crest-specific transgene (Li et al., 2005b). Assays in mouse embryonic palatal mesenchyme cells (MEPMs) indicated that stimulation with the secreted ligands fibroblast growth factor (FGF) or platelet-derived growth factor (PDGF) promoted SRF-TCF complex formation, but only PDGF promoted SRF-MRTF interactions, in a PI3K-dependent manner (Vasudevan and Soriano, 2014). Supporting the importance of SRF-MRTF interactions, Srf interacted genetically with Pdgfra but not Fgfr1 in NC (Vasudevan and Soriano, 2014). However, the contributions of each SRF-cofactor transcriptional program to the overall Srf NC phenotype are unclear.

In this study, we further characterize the molecular consequences of losing Srf expression in the NC through marker analysis and expression profiling, finding the most highly downregulated genes to be cytoskeletal in nature. We then test the presumed requirement of SRF-MRTF interactions using a novel Srf^aI allele carrying mutations that prevent SRF-MRTF-DNA ternary complex formation to circumvent MRTF redundancy and control for possible SRF-independent MRTF activity. These embryos have striking developmental defects that are outwardly similar to Myocd mutant mice. Conditional NC mutants reveal an essential role for optimal SRF-MRTF activity in the cardiac crest, whereas the mutation is well-tolerated in the cranial NC. These observations raise the possibility that non-cardiovascular tissue may be able to develop with only minimal SRF-MRTF activity or that SRF can support cytoskeletal gene expression on its own or with other cofactors.

SRF is a ubiquitously expressed transcription factor whose transcriptional output is strongly influenced by its cofactors, the TCFs and MRTFs. These cofactors, in turn, are regulated both by specific expression patterns (e.g. Myocd specifically in muscle) and by signaling pathways, such as ERK1/2 and PI3K (Posern and Treisman, 2006; Figure 1A). We sought to better understand the relationship between SRF, its cofactors, and mutant phenotypes in both a general and a tissue-specific manner.

Our previous study demonstrated a requirement for Srf in the NC lineage (Vasudevan and Soriano, 2014), so we first investigated how loss of SRF in this tissue affected gene expression. We found normal early NC patterning but misexpression of cytoskeleton-related genes in Srf^flox/flox; Wnt1-Cre^Tg/+ embryos (Figure 1C–F, Figure 1—figure supplements 1 and 2E). Comparing the DEGs with known SRF and cofactor targets showed particular enrichment for MRTF targets in our datasets (Figure 1G–H, Figure 1—figure supplement 2F-G), consistent with SRF’s well-known function regulating cytoskeletal genes and the dominant role of MRTF cofactors in the serum response (Esnault et al., 2014). To test the supposition that SRF-MRTF activity would be the main driver of NC SRF activity, we made a new Srf^aI mouse model harboring point mutations that specifically disrupt SRF-MRTF-DNA complex formation (Zaromytidou et al., 2006).

Homozygous Srf^aI/aI embryos died at E10.5 with defects in the yolk sac vasculature, heart, and neural tube and exhibited reduced F-actin levels (Figure 2A–F). Both the timing of lethality and gross appearance of the embryos strongly resemble Myocd^-/- mutant mice (Li et al., 2003). The phenotype is much less severe than Srf^-/- embryos, however, which die around E7.5 and fail to induce mesoderm (Arsenian et al., 1998; Niu et al., 2005). Expression of the Srf^aI allele specifically in the Mesp1^Cre mesodermal lineage also resulted in lethality at E10.5 and defects almost as severe as complete loss of Srf in this same lineage (Figure 3). The similarity of the two alleles in the Mesp1^Cre lineage compared against their strikingly different phenotypes in gastrula-stage embryos suggested there may be time or tissue specific requirements for SRF-MRTF activity.

We went on to test the Srf^aI allele in the NC lineage, where we presumed it would be critically important. Similar to the early embryo, expression of the Srf^aI allele was well tolerated in NC and we found no facial cleft or bleb in our Srf^aI/flox; Wnt1-Cre^Tg/+ mice, as in Srf^flox/flox; Wnt1-Cre^Tg/+ mice (Figure 4A). The allele also failed to interact genetically with Pdgfra in this lineage, suggesting PDGF signaling may rely on MRTF-independent SRF activity (Figure 5—figure supplement 2A-B). Nevertheless, this mutation in NC does have a profound developmental effect as Srf^aI/flox; Wnt1-Cre^Tg/+ mice completed gestation but died by postnatal day 2 with visible cyanosis (Figure 5A). Examination of the cardiac outflow tract revealed numerous defects including PDA, right aortic arch, and one instance of VSD with PTA (Figure 5C–D). This result is reminiscent of mice with a hypomorphic gene trap mutation in Mrtfb and mice carrying a conditional deletion of Myocd in the NC (Huang et al., 2008; Li et al., 2005b), both of which result in early postnatal lethality due to defects in outflow tract development. Similarly, NC conditional Srf mutants on a genetic background that permitted later development exhibit outflow tract defects at E16.5 (Newbern et al., 2008). These studies and our own results together highlight a critical role for SRF-MRTF interactions in cardiac NC development. A summary of the tissue-specific sensitivities we found to loss of Srf or Srf^aI expression is depicted in Figure 5E.

We considered three possible explanations for the tolerance of the Srf^aI allele in NC and early embryo, which are not mutually exclusive: (i) that TCFs are more important than previously recognized or are redundant with MRTFs in some respects, (ii) that different tissues may have different thresholds for SRF-MRTF activity and that our point mutant may interact differently with different MRTF family members, and (iii) that SRF may utilize cofactors other than MRTFs and TCFs or have cofactor-independent (i.e. basal) activity sufficient to support development in some contexts.

The first possibility is that TCF factors play a more important role than previously thought or can act redundantly with MRTFs. Because TCF triple mutant embryos survive until E14.5 without obvious morphological defects (Costello et al., 2010), we find it unlikely that TCF-specific activity could explain the tolerance of Srf^aI during gastrulation or in NC. However, it has been shown that some SRF targets can be bound and regulated by both MRTF and TCF factors (Esnault et al., 2014), raising the possibility of cofactor redundancy. Yet, most studies to date indicate that rather than acting redundantly, MRTFs and TCFs mediate distinct and opposing phenotypic outcomes, contractility and proliferation, respectively (Gualdrini et al., 2016; Wang et al., 2004). Indeed, a potential result of this competition is that the consequences of suppressing SRF-MRTF interactions could vary according to the level of TCF expression in a given cell type. While we cannot rule out the possibility that TCFs are the primary SRF cofactors in NC or function redundantly to MRTFs without further genetic experiments, this explanation is difficult to reconcile with the existing literature. Although there is no known Srf allele that blocks TCF binding while leaving MRTF binding unperturbed, the V194E mutation (V189E in mouse) disrupts SRF interaction with both cofactors (Ling et al., 1998). Generating a mouse model of this allele would shed considerable light on the question of TCF/MRTF redundancy.

A second explanation is that non-muscle lineages may be able to function with minimal, but not zero, SRF-MRTF activity. It is possible that the Srf^aI allele substantially impairs but does not eliminate SRF-MRTF-DNA complex formation and functions as a hypomorph. In vitro gel shift assays for SRF-MRTF-DNA complex formation using purified components and single molecule imaging of SRF in cells both indicate a substantial disruption of SRF-MRTF activity for this allele, but the gel shift experiments that first characterized these mutations detected 5–10% residual complex formation (Hipp et al., 2019; Zaromytidou et al., 2006). Our own data demonstrate that homozygous Srf^aI/aI embryos grossly phenocopy Myocd^-/- mutants (Figure 2) and Srf^aI/flox; Mesp1-Cre^Tg/+ and Srf^flox/flox; Mesp1-Cre^Tg/+ embryos were similar, though not identical (Li et al., 2003). On the other hand, double conditional mutants for Mrtfa/Mrtfb largely do phenocopy Srf conditional mutants in several tissues (Cenik et al., 2016; Guo et al., 2018; Li et al., 2005a; Trembley et al., 2015). Therefore, we may be observing differing dosage requirements for SRF-MRTF activity in distinct tissues. Muscle lineages, such as cardiovascular cells affected by Mesp1^Cre and NC-derived outflow tract smooth muscle affected by Wnt1-Cre, may need optimal SRF-MRTF output and are therefore strongly affected by the Srf^aI allele. Non-muscle lineages such as the cranial NC may survive and develop properly with only residual SRF-MRTF transcription. The Srf^aI allele might more strongly suppress Myocardin compared to MRTFA/B, which could also contribute to the tissue-specific requirements we observe. Two predictions of this threshold model are that conditional ablation of Mrtfa/Mrtfb in NC would phenocopy conditional loss of Srf and that Mrtfa/Mrtfb double mutant embryos should succumb around E7.5 as Srf null embryos do. Conversely, non-muscle lineages where conditional ablation of Mrtfa/Mrtfb yields Srf-like phenotypes, such as podocytes and epicardium, should be indifferent to the Srf^aI mutations.

The issue of SRF tissue-specific dosage effects may have relevance to human disease. A recent study performed targeted sequencing of SRF in nonsyndromic conotruncal heart defect patients and identified two novel mutations with reduced transcriptional output, one from a patient with VSD and the other with Tetralogy of Fallot with right aortic arch (Mengmeng et al., 2020). Thus, tuning of SRF output may modulate disease in a tissue-specific manner. Along these lines, mutations in MYOCD cause congenital megabladder and associated cardiovascular phenotypes such as PTA and VSD in humans, but monoallelic mutations affect only males whereas biallelic mutations affect both sexes (Houweling et al., 2019). Furthermore, heterozygosity for FLNA, a gene we found strongly affected by loss of Srf in mouse NC, causes the human disease Periventricular Heterotopia I and affected females present with PDA, whereas hemizygous males die during gestation (Fox et al., 1998). Intriguingly, NC-specific conditional knockout of Flna causes perinatal lethality with outflow tract defects in mice (Feng et al., 2006). It would be interesting to further explore the notion of tissue-specific thresholds for SRF-cofactor complexes in future studies.

A third explanation is that SRF functions with additional factors that regulate gene expression independent of or redundantly with MRTFs (and/or TCFs) or has sufficient basal activity to support development in some tissues. Although MRTFs and TCFs are the most well-studied SRF cofactors, many other TFs have been shown to interact with SRF, including but not limited to Homeodomain proteins (Chen et al., 1996; Chen et al., 2002; Grueneberg et al., 1992; Shin et al., 2002), GATA factors (Belaguli et al., 2000; Morin et al., 2001), and Forkhead-family transcription factors (Freddie et al., 2007; Liu et al., 2005), as well as the Initiator-binding protein TFII-I (Grueneberg et al., 1997; Kim et al., 1998). Many of these studies were performed in muscle cells and it is unclear which cofactors might act independently of MRTFs. However, several of these genes or their orthologues are expressed in the cranial NC at E10.5 and E11.5, when cleft formation begins in Srf^flox/flox; Wnt1-Cre^Tg/+ embryos (Minoux et al., 2017). One candidate is the homeodomain protein PRRX1/PHOX1/MHOX, which was shown to form complexes with SRF mediated by TFII-I (Grueneberg et al., 1997). Double mutants for Prrx1 and its orthologue Prrx2 have defects of the craniofacial skeleton, aortic arch arteries, and ductus arteriosus (Bergwerff et al., 2000; Lu et al., 1999). Gtf2i mutants (the gene encoding TFII-I) rarely survive past E10.5 but can exhibit a facial cleft, hemorrhaging, and hypoplastic pharyngeal arches (Enkhmandakh et al., 2009). Whether SRF mediates transcription on its own, independently of MRTFs and TCFs, or perhaps using additional tissue-specific cofactors, would be exciting to determine.

In conclusion, we found that the primary transcriptional consequence of losing Srf in NC was a defect in actin cytoskeleton-related gene expression. Using a novel Srf^aI allele to perturb SRF’s interactions with MRTFs, the primary cofactors regulating the cytoskeletal transcription program, we uncovered a crucial role for SRF-MRTF activity in the cardiac NC, but surprisingly found the mutation well-tolerated in the cranial NC. Further study will be necessary to determine the relevant SRF-cofactor ensembles in different developmental contexts.

The NGS data is available on GEO. https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE186770.

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Author details

1. Colin J Dinsmore

   Department of Cell, Development and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Validation, Visualization, Writing - original draft, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-6404-1202

2. Philippe Soriano

   Department of Cell, Development and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, United States

   Contribution

   Conceptualization, Funding acquisition, Investigation, Project administration, Supervision, Writing - review and editing

   For correspondence

   philippe.soriano@mssm.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-0427-926X

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