Table 1. Developmental Pathways.

The 2000 National Research Council report, Scientific Frontiers in Developmental Toxicology and Risk Assessment, proposed 17 consensual cell-cell signaling pathways that are hallmarks of morphogenesis (NRC 2000; Abbott 2008). Here, we add the Per-ARNT-Sim (PAS) pathway, which consists of the hypoxia, circadian, and aryl hydrocarbon receptor (AHR) pathways (McIntosh et al. 2010; Hahn and Karchner 2012; Brown 2014). Some signaling intermediates are shared by different developmental pathways, such as mitogen-activated protein kinases (MAPK) and activator protein 1 (AP-1) by both small G-protein (Ras)-linked receptor tyrosine kinase and receptor guanylate cyclase pathways.

Embryonic Stages	Developmental Pathways	Ligands, Receptors, and Signaling Intermediates
Early development and later	1a and 1b. Wingless-int (Wnt) pathway (canonical and noncanonical)	Wnt proteins, β catenin, and jun N-terminal kinase (JNK)
	2. Receptor serine-threonine kinase pathway	Transforming growth factor β (TGFβ), bone morphogenetic proteins (BMPs), and Smad transcription factors
	3. Sonic hedgehog (Shh) pathway	Shh, patched receptor (Ptc), and smoothened (Smo)
	4. Small G-protein (Ras)-linked receptor tyrosine kinase pathway	Epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), insulin-like growth factor, ephrins, protein kinase C (PKC), Ras, Rho, extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase (MAPK), and jun N-terminal kinase (JNK/p38)
	5. Notch-Delta pathway	Notch, Delta, Jagged, and Serrate
	6. Cytokine receptor pathway	Growth hormone, erythropoietin, prolactin, thrombopoietin, interleukins, interferons, and Janus kinase (JAK)/signal transducer and activator of transcription protein (STAT)
	7. Per-ARNT-Sim (PAS) pathway	Hypoxia-inducible factor (HIF), aryl hydrocarbon receptor (AHR), RAR-related orphan receptor A (RORA), heat shock protein 90 (HSP90), AHR repressor, nuclear translocator, and nuclear translocator-like (AHRR ARNT, and ARNTL), clock circadian regulator (CLOCK), and period and cryptochrome circadian clock (PER and CRY)
Organogenesis and later	8. Interleukin-1 receptor pathway	Nuclear factor-Kappa B (NFκB) and inhibitors (IκB)
	9. Nuclear hormone receptor pathway	Estrogen receptor (ER), glucocorticoid receptor (GR), mineralocorticoid receptor (MR), androgen receptor (AR), prostaglandin receptor (PR), thyroid hormone receptor (TR), vitamin D3 receptor (VDR), retinoic acid receptor (RAR), retinoid X receptor (RXR), and peroxisome proliferator-activated receptor (PPAR)
	10. Apoptosis pathway	Caspase proteolytic enzymes, tumor necrosis factor, Fas, BAX, Bcl2, FADD, and TRADD
	11. Receptor phosphotyrosine phosphatase pathway	Dephosphorylation of receptors and intermediates of other pathways
Postdifferentiation	12. Receptor guanylate cyclase pathway	c-Fos, JunB, cyclic AMP response element-binding protein (CREB), activator protein 1 (AP-1), and ion channels
	13. Nitric oxide receptor pathway	A cytoplasmic enzyme that binds NO at a heme group converting GTP to cyclic GMP and affecting transcription via c-Fos
	14. G-protein-coupled receptor (large G proteins) pathway	A very broad range of ligands (proteins, peptides, and small molecules) that bind cell-surface receptors and affect a broad range of events (transcription, metabolism, motility, secretion, and activity of other kinase pathways)
	15, 16, and 17. Integrin, cadherin, and gap pathways	Cell-to-cell signaling and cell-environment signaling that affect adhesion, motility, and passage of ions, metabolites and signaling molecules between cells
	18. Ligand-gated cation channel pathways	Several receptors and ligands (acetylcholine, glutamate, NMDA, and GABA) and affect membrane potentials and calcium-dependent events