Mapping the temporal and functional landscape of Sonic Hedgehog signaling reveals new insights into early human forebrain development
Panasenkava, V.; Garreau, J.; Guyodo, H.; Diab, F.; Mahieux, A.; Carre, W.; Verres, Y.; Jullion, E.; Odent, S.; Dubourg, C.; Rollier, P. R.; Dubos, L.; RIBES, V.; Camus, A.; Tayrac, M.; Dupe, V.
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The early patterning of the anterior neuroectoderm constitutes a fundamental blueprint for human brain development, orchestrated by multiple signaling pathways. Among them, Sonic Hedgehog (SHH) plays a key influence. However, the transcriptional programs it engages remain poorly defined due to the limited accessibility of human brain tissue. To address this, we established a human induced pluripotent stem cells-derived model of early forebrain differentiation, enabling a precise dissection of SHH-driven transcriptional programs over time. RNA sequencing revealed dynamic transcriptomic landscapes governing forebrain neuroectoderm specification and dorsoventral patterning. In addition, pharmacological perturbation of SHH signaling allowed to identify an extended collection of novel forebrain regionalization markers, including several previously unrecognized dorsal and ventral determinants. By combining in vivo human datasets with functional mouse studies, we enhanced the biological relevance of this extended network of putative SHH-regulated genes and long non-coding RNAs in shaping early forebrain architecture. This work advances our understanding of the temporal dynamics of SHH signaling in human neurodevelopment and provide critical molecular insights into midline brain malformations. It offers a promising foundation for advancing molecular diagnosis of complex rare genetic disorders. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=166 SRC="FIGDIR/small/654466v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@dac307org.highwire.dtl.DTLVardef@3a051borg.highwire.dtl.DTLVardef@12559c9org.highwire.dtl.DTLVardef@129cbec_HPS_FORMAT_FIGEXP M_FIG C_FIG
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