Two types of distinct cardiac progenitor cell populations can be identified during early heart development: the first heart field (FHF) and second heart field (SHF) lineage that later form the mature heart. They can be characterized by differential expression of transcription and signaling factors. These regulatory factors influence each other forming a gene regulatory network. Here, we present a core gene regulatory network for early cardiac development based on published temporal and spatial expression data of genes and their interactions. This gene regulatory network was implemented in a Boolean computational model. Simulations reveal stable states within the network model, which correspond to the regulatory states of the FHF and the SHF lineages. Furthermore, we are able to reproduce the expected temporal expression patterns of early cardiac factors mimicking developmental progression. Additionally, simulations of knock-down experiments within our model resemble published phenotypes of mutant mice. Consequently, this gene regulatory network retraces the early steps and requirements of cardiogenic mesoderm determination in a way appropriate to enhance the understanding of heart development. Helikar Tomas thelika@unmc.edu University of Nebraska - Lincoln 2013-06-06T05:52:12Z 2017-07-19T14:23:23Z

External signaling factor BMP2 number 1<div><br/></div>

2015-11-15T17:58:42Z

Exogenous canonical Wnt signaling II

2015-11-15T17:58:42Z

Transcription factor GATA-4 (human)<div>UniProt AccessionID: <a href="http://www.uniprot.org/uniprot/P43694" style="font-size: small; text-decoration: none; font-family: sans-serif; background-color: rgb(255, 255, 255);">P43694</a></div><div>Transcription factor GATA-4 (mouse)<div>UniProt AccessionID: <a href="http://www.uniprot.org/uniprot/Q08369" style="font-size: small; text-decoration: none; font-family: sans-serif; background-color: rgb(255, 255, 255);">Q08369</a></div></div>

2015-11-15T17:58:42Z

Transcription factor Mesp1 <div>Human<br/><div>UniProt AccessionID: <a href="http://www.uniprot.org/uniprot/Q9BRJ9" style="font-size: small; text-decoration: none; font-family: sans-serif; background-color: rgb(255, 255, 255);">Q9BRJ9</a></div></div><div>Mouse</div><div>UniProt AccessionID: <a href="http://www.uniprot.org/uniprot/P97309" style="font-size: small; text-decoration: none; font-family: sans-serif; background-color: rgb(255, 255, 255);">P97309</a></div>

2015-11-15T17:58:42Z

T-box transcription factor 1<div>Mouse</div><div>UniProt AccessionID: <a href="http://www.uniprot.org/uniprot/P70323" style="font-size: small; text-decoration: none; font-family: sans-serif; background-color: rgb(255, 255, 255);">P70323</a></div>

2017-05-15T14:35:46Z

<span style="font-family: arial, helvetica, clean, sans-serif; line-height: 17px; background-color: rgb(255, 255, 255);">LIM homeodomain transcription factor </span><span class="highlight" style="font-family: arial, helvetica, clean, sans-serif; line-height: 17px; background-color: rgb(242, 245, 248);">Islet1 (mouse)</span><div><font face="arial, helvetica, clean, sans-serif"><span style="line-height: 17px;">UniProt AccessionID: </span></font><a href="http://www.uniprot.org/uniprot/A2RSV5" style="text-decoration: none; font-family: sans-serif; font-size: small; background-color: rgb(255, 255, 255);">A2RSV5</a><font face="arial, helvetica, clean, sans-serif"><span style="line-height: 17px;"><br/></span></font><div style="font-family: Arial, Verdana; line-height: normal;"><span class="highlight" style="background-color: rgb(242, 245, 248); font-family: arial, helvetica, clean, sans-serif; line-height: 17px;"><br/></span></div><div style="font-family: Arial, Verdana; line-height: normal;"><span class="highlight" style="background-color: rgb(242, 245, 248); font-family: arial, helvetica, clean, sans-serif; line-height: 17px;"><br/></span></div></div>

2015-11-15T17:58:42Z

<div>Bone morphogenetic protein 2 (mouse)</div>Endothermal signal<div>UniProt Accession ID: <a href="http://www.uniprot.org/uniprot/P21274" style="font-size: small; text-decoration: none; font-family: sans-serif; background-color: rgb(255, 255, 255);">P21274</a></div>

2015-11-15T17:58:42Z

Early cardiac regulatory gene Nkx-2.5<div>Human</div><div>UniProt AccessionID: <a href="http://www.uniprot.org/uniprot/P52952" style="text-decoration: none; font-family: sans-serif; font-size: small; background-color: rgb(255, 255, 255);">P52952</a></div><div>Mouse</div><div>UniProt AccessionID: <a href="http://www.uniprot.org/uniprot/P42582" style="text-decoration: none; font-family: sans-serif; font-size: small; background-color: rgb(255, 255, 255);">P42582</a><br/><div><br/><div><br/></div></div></div>

2015-11-15T17:58:42Z

Forkhead box protein C1<div>UniProt AccessionID: <a href="http://www.uniprot.org/uniprot/Q12948" style="font-size: small; text-decoration: none; font-family: sans-serif; background-color: rgb(255, 255, 255);">Q12948</a></div><div>Forkhead box protein C2</div><div>UniProt AccessionID: <a href="http://www.uniprot.org/uniprot/Q99958" style="font-size: small; text-decoration: none; font-family: sans-serif; background-color: rgb(255, 255, 255);">Q99958</a></div>

2015-11-15T17:58:42Z

T-box transcription factor TBX5

Gene Name: TBX5

UniProt ID: Q99593

Gene ID: 6910

FHF transcription factor

2017-05-15T14:35:46Z

Fibroblast growth factor 8 (mouse)<div>UniProt Accession ID: <a href="http://www.uniprot.org/uniprot/P37237" style="font-size: small; text-decoration: none; font-family: sans-serif; background-color: rgb(255, 255, 255);">P37237</a></div><div>Fibroblast growth factor 8 (human)<div>UniProt Accession ID: <a href="http://www.uniprot.org/uniprot/P55075" style="font-size: small; text-decoration: none; font-family: sans-serif; background-color: rgb(255, 255, 255);">P55075</a></div></div>

2015-11-15T17:58:42Z

Exogenous BMP2

2015-11-15T17:58:42Z

<div>(Human)</div>Uniprot Accession ID: <a href="http://www.uniprot.org/uniprot/O94907" style="text-decoration: none; font-family: sans-serif; font-size: small; background-color: rgb(255, 255, 255);">O94907</a><div>(Mouse)</div><div>UniProt Accession ID: <a href="http://www.uniprot.org/uniprot/O54908" style="font-size: small; text-decoration: none; font-family: sans-serif; background-color: rgb(255, 255, 255);">O54908</a></div>

2015-11-15T17:58:42Z

Canonical Wnt signaling<div>Wnt-3a (mouse)</div><div>UniProt Accession ID: <a href="http://www.uniprot.org/uniprot/P27467" style="font-size: small; text-decoration: none; font-family: sans-serif; background-color: rgb(255, 255, 255);">P27467</a></div>

2017-05-15T14:35:46Z

Exogenous canonical Wnt signaling

2015-11-15T17:58:42Z

exong_canWnt_I positively regulates exogen_canWnt_II [1].

exong_canWnt_I positively regulates exogen_canWnt_II {[1]}

S_15 1

Nkx2_5, Mesp1, and Tbx5 all independently up regulate GATAs [1,2,3,4,5,6].

Mesp1 positively regulates GATAs {[1][2][3][4]}

Tbx5 up regulates GATAs {[1][6]}

Nkx2_5 positively regulates GATAs {[1][5]}

S_3 1 S_9 1 S_7 1

canWnt positively regulates Mesp1 [1,2]. exogen_BMP2_II negatively regulates Mesp1 [1].

Early canonical Wnt is required for the cardiac specific activation of Mesp1 {[1][2]}

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">exogen_BMP2_II negatively regulates Mesp1 {[1]}</span>

S_14 1 S_11 1

Foxc1_2 positively regulates Tbx1 [1,2,3].

Foxc1_2 positively regulates Tbx1 {[1][2][3]}

S_8 1

CanWnt in conjunction with exogen_canWnt_II up regulates Isl1 [1,2,3]. Fgf8 positively regulates Isl1 [1,4]. Mesp1 positively regulates Isl1 [1,5,6]. Tbx1 positively regulates Isl1 [1,7].

canWnt in conjunction with exogen_canWnt_II up regulates Isl1 {[1][2][3]}

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Mesp1 positively regulates Isl1 {[1][5][6]}</span>

canWnt in conjunction with exogen_canWnt_II up regulates Isl1 {[1][2][3]}

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Fgf8 positively regulates Isl1 {[1][4]}</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Tbx1 positively regulates Isl1 {[1][7]}</span>

S_4 1 S_14 1 S_1 1 S_3 1 S_10 1

Bmp2 is negatively regulated by canWnt [1,2]. Bmp2 is positively regulated by exogen_BMP2_II [1].

S_11 1 S_14 1

GATAs in conjunction with either Isl1 or Bmp2 up regulate Nkx2_5 [1,2,3,4].  Mesp1 and Dkk1 in conjunction positively regulates Nkx2_5 [1,5,6,7]. Tbx1 positively regulates Nkx2_5 [1,2]. Tbx5 positively regulates Nkx2_5 [1,2,8]. 

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Isl1 and GATAs in conjunction up-regulate Nkx2_5 {[1][2][3]}</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Bmp2 and GATAs in conjunction positively regulate Nkx2_5 {[1][3][4]}</span><div><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Isl1 and GATAs in conjunction up-regulate Nkx2_5 {[1][2][3]}</span></div>

S_3 1 S_13 1 S_6 1 S_2 1 S_5 1 S_2 1 S_9 1 S_4 1

canWnt and exogen_canWnt_II independently positively regulate Foxc1_2 [1,2,3].

canWnt positively regulates Foxc1_2 {[1][2][3]}

exogen_canWnt_II independently positively regulates Foxc1_2 {[1]}

S_14 1 S_1 1

Mesp1 activates Tbx5. Dkk1 inhibits Tbx5 when Mesp1 and Tbx5 are inactive. Tbx1 inhibits Tbx5. Tbx5 activates Tbx5. canWnt inhibits Tbx5. Nkx2_5 activates Tbx5.

Mesp1 upregulates Tbx5 expression.

canWnt downregulates Tbx5.

Nkx2_5 upregulates Tbx5 expression.

Tbx5 upregulates Tbx5 expression.

Tbx1 downregulates Tbx5 expression.

Dkk1 downregulates Tbx5 expression.

S_9 1 S_4 1 S_14 1 S_13 1 S_3 1 S_9 1 S_3 1 S_4 1 S_14 1 S_13 1 S_3 1 S_9 1 S_7 1 S_4 1 S_14 1 S_13 1 S_3 1 S_9 1

Foxc1_2 or Tbx1 positively regulate Fgf8 [1,2,3]. Mesp1 negatively regulates Fgf8 [1,4].

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Foxc1_2  positively regulates Fgf8 {[1][2]}</span>

S_4 1 S_3 1 S_8 1 S_3 1

exogen_BMP2_I positively regulates exogen_BMP2_II [1].

exogen_BMP2_I positively regulates exogen_BMP2_II {[1]}

S_12 1

Mesp1 positively regulates Dkk1 [1,3]. canWnt and not exogen_BMP2_II in conjunction regulate Dkk1 [1,2].

<span style="color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18px; background-color: rgb(255, 255, 255);">*Following an active canonical Wnt signaling Mesp1 and Dkk1 are expressed [1,2].</span><div><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*canWnt and not exogen_BMP2_II in conjunction regulate Dkk1 [1,2].</span></div>

<span style="color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18px; background-color: rgb(255, 255, 255);">Following an active canonical Wnt signaling Mesp1 and Dkk1 are expressed[1,3].</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">canWnt and not exogen_BMP2_II in conjunction regulate Dkk1 [1,2].</span>

S_14 1 S_11 1 S_3 1

exogen_canWnt_II positively regulates canWnt [1].

exogen_canWnt_II positively regulates canWnt [1]

S_1 1

exogen_CanWnt_I is regulated by iteself [1].

exogen_CanWnt_I is regulated by iteself {[1]}

S_15 1