The cerebral cortex is divided into many functionally distinct areas. The emergence of these areas during neural development is dependent on the expression patterns of several genes. Along the anterior-posterior axis, gradients of Fgf8, Emx2, Pax6, Coup-tfi, and Sp8 play a particularly strong role in specifying areal identity. However, our understanding of the regulatory interactions between these genes that lead to their confinement to particular spatial patterns is currently qualitative and incomplete. We therefore used a computational model of the interactions between these five genes to determine which interactions, and combinations of interactions, occur in networks that reproduce the anterior-posterior expression patterns observed experimentally. The model treats expression levels as Boolean, reflecting the qualitative nature of the expression data currently available. We simulated gene expression patterns created by all possible networks containing the five genes of interest. We found that only of these networks were able to reproduce the experimentally observed expression patterns. These networks all lacked certain interactions and combinations of interactions including auto-regulation and inductive loops. Many higher order combinations of interactions also never appeared in networks that satisfied our criteria for good performance. While there was remarkable diversity in the structure of the networks that perform well, an analysis of the probability of each interaction gave an indication of which interactions are most likely to be present in the gene network regulating cortical area development. We found that in general, repressive interactions are much more likely than inductive ones, but that mutually repressive loops are not critical for correct network functioning. Overall, our model illuminates the design principles of the gene network regulating cortical area development, and makes novel predictions that can be tested experimentally. Helikar Tomas thelika@unmc.edu University of Nebraska - Lincoln 2013-03-17T12:46:02Z 2016-01-22T07:08:46Z

<font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Empty spiracles homeobox 2 [</span><em style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"> (human)]</span></font><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/Q04743" style="text-decoration: none; background-color: rgb(255, 255, 255);">Q04743</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/2018" ref="ordinalpos=2&ncbi_uid=2018&link_uid=2018" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">EMX2</span></a></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 17.77777862548828px;">2018</span></font></div>

2015-11-15T17:39:12Z

<font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Paired box 6 [</span><em style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">(human)]</span></font><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P26367" style="text-decoration: none; background-color: rgb(255, 255, 255);">P26367</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/5080" ref="ordinalpos=2&ncbi_uid=5080&link_uid=5080" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">PAX6</span></a></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 17.77777862548828px;">5080</span></font></div>

2015-11-15T17:39:12Z

<div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);"><span style="line-height: 18.88888931274414px;">Nuclear receptor subfamily 2, group F, member 1 [</span><em style="line-height: 18.88888931274414px;">Homo sapiens</em><span style="line-height: 18.88888931274414px;"> (human)]</span></font></div><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);">UniProt ID :<a href="http://www.uniprot.org/uniprot/P10589" style="text-decoration: none;">P10589</a></font></div><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/7025" ref="ordinalpos=1&ncbi_uid=7025&link_uid=7025" style="line-height: 18.88888931274414px; white-space: nowrap;">NR2F1</a></font></div><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);">Gene ID: <span style="line-height: 17.77777862548828px;">7025</span></font></div>

2015-11-15T17:39:12Z

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>

2015-11-15T17:39:12Z

<font face="Georgia" size="2"><span class="highlight" style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Sp8</span><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"> transcription factor [</span><em style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"> (human)]</span></font><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/Q8IXZ3" style="text-decoration: none; background-color: rgb(255, 255, 255);">Q8IXZ3</a><span style="background-color: rgb(255, 255, 255); line-height: 18.88888931274414px;"> </span></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/221833" ref="ordinalpos=2&ncbi_uid=221833&link_uid=221833" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">SP8</span></a></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 17.77777862548828px;">221833</span></font></div>

2015-11-15T17:39:12Z

<font face="Georgia" size="2">Coup fti activates Emx2 while Fgf8, Pax6 and Sp8 all inactivate Emx2 [1]. </font>

<font face="Georgia" size="2">Fgf8 inhibits Emx2 [1,4,5,6,7,8,9]. </font>

<span style="font-family: Georgia; font-size: small;">Coup fti activates Emx2 [1,2,3]. </span>

<span style="font-family: Georgia; font-size: small;">Pax6 inhibits Emx2 [1,10]. </span>

<span style="font-family: Georgia; font-size: small;">Sp8 inhibits Emx2 [1,11]. </span>

S_3 1 S_4 1 S_5 1 S_2 1

<font face="Georgia" size="2">Sp8 activates Pax6. Coup ftI and emx2 inhibit Pax6 and are dominant over sp8 [1]. </font>

<span style="font-family: Georgia; font-size: small;">EMX2 inhibits Pax6 [1, 4,5]. 22 55</span>

<font face="Georgia" size="2">Coup fti inhibits Pax6 [1, 2,3]. 23,28</font>

<font face="Georgia" size="2">Sp8 activates Pax6 [1,6]. 26</font>

S_5 1 S_3 1 S_1 1

<font face="Georgia" size="2">Both Fgf8 and Sp8 are inhibitors of Coup fti [1]. </font>

<font face="Georgia" size="2">Fgf8 inhibits Coup fti [1,2,3,4,5]. </font>

<font face="Georgia" size="2">Sp8 inhibits Coup fti [1,6]. </font>

S_4 1 S_5 1 S_4 1 S_5 1

<font face="Georgia" size="2">Fgf8 activates Fgf8 [1,5,6,7]. </font>

<font face="Georgia" size="2">Emx2 inhibits Fgf8 [1,2,3,4]</font><span style="font-size: 10pt; font-family: Arial, Verdana;">. </span>

<font face="Georgia" size="2">Sp8 activates Sp8 [1,8,9].</font><span style="font-size: 10pt; font-family: Arial, Verdana;"> </span>

S_4 1 S_5 1 S_1 1

<font face="Georgia" size="2">Fgf8 activates Sp8, while Emx2 inhibits Sp8 and is dominant over Fgf8 [1]. </font>

<font face="Georgia" size="2">Fgf8 activates Sp8 [1,2,3]. </font>

<font face="Georgia" size="2">Emx2 inhibts Sp8 [1,2,3,4].</font>

S_4 1 S_1 1