Target type: biologicalprocess
The regionalization process in which the area where the ventral midline will form is specified. [GOC:bf, GOC:isa_complete, GOC:vk]
Ventral midline determination is a crucial developmental process that establishes the central axis of the embryo, laying the foundation for the formation of essential structures like the nervous system and the digestive tract. This process is orchestrated by a complex interplay of signaling pathways and transcription factors, starting with the specification of the ventral midline itself.
The first step involves the activation of the **Hedgehog (Hh) signaling pathway** at the ventral midline. Hh proteins, secreted by cells in the notochord and floor plate, bind to their receptor Patched (Ptc) on adjacent cells. This binding relieves the inhibition of Smoothened (Smo), a transmembrane protein, allowing it to activate downstream signaling cascades.
These cascades ultimately lead to the activation of transcription factors, particularly **Gli1, Gli2, and Gli3**. The precise outcome depends on the level of Hh signaling: high levels activate Gli1 and Gli2, leading to expression of ventral midline-specific genes. Conversely, low levels of Hh activate the repressor form of Gli3, suppressing the expression of dorsal genes.
The interplay of Hh signaling and Gli transcription factors regulates the expression of genes that define ventral midline identity, including:
* **Shh (Sonic Hedgehog):** Acts as a key morphogen, setting up a gradient of Hh signaling along the anterior-posterior axis, which influences the development of different cell types.
* **Noggin:** An antagonist of the bone morphogenetic protein (BMP) pathway, preventing the formation of dorsal structures.
* **Chordin:** Another BMP antagonist, further reinforcing the suppression of dorsal fates.
* **Foxa2:** A transcription factor that plays a crucial role in the development of the floor plate, a specialized cell population that provides essential signals for neural tube formation.
* **Nkx2.2:** Another transcription factor required for the development of the floor plate and the formation of motor neurons.
These genes, regulated by Hh signaling and Gli transcription factors, establish the ventral midline as a distinct domain, defining its fate and allowing for the formation of specialized structures along the ventral axis of the embryo.'
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| Protein | Definition | Taxonomy |
|---|---|---|
| Smoothened homolog | A protein smoothened that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q99835] | Homo sapiens (human) |
| Compound | Definition | Classes | Roles |
|---|---|---|---|
| cyclopamine | piperidines | glioma-associated oncogene inhibitor | |
| pd 173955 | PD 173955: inhibits src family-selective tyrosine kinase; structure in first source | aryl sulfide; dichlorobenzene; methyl sulfide; pyridopyrimidine | tyrosine kinase inhibitor |
| purmorphamine | purmorphamine : A member of the class of purines that is purine substituted at C-2 by a 1-naphthyloxy group, at C-4 by a 4-morpholinophenylamino group, and at N-9 by a cyclohexyl group. purmorphamine: structure in first source | aromatic ether; morpholines; purines; secondary amino compound | osteogenesis regulator; SMO receptor agonist |
| cur 61414 | CUR 61414: inhibits the hedehog signaling pathway; structure in first source | ||
| abt 869 | aromatic amine; indazoles; phenylureas | angiogenesis inhibitor; antineoplastic agent; EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor | |
| lde225 | sonidegib : A member of the classo of biphenyls that is the amide obtained by formal condensation of the carboxy group of 2-methyl-4'-(trifluoromethoxy)[1,1'-biphenyl]-3-carboxylic acid with the amino group of 6-(2,6-dimethylmorpholin-4-yl)pyridin-3-amine. Used (as its phosphate salt) for treatment of locally advanced basal cell carcinoma. sonidegib: specific Smoothened/Smo antagonist | aminopyridine; aromatic ether; benzamides; biphenyls; morpholines; organofluorine compound; tertiary amino compound | antineoplastic agent; Hedgehog signaling pathway inhibitor; SMO receptor antagonist |
| gdc 0449 | HhAntag691: inhibits the hedgehog pathway and ABC transporters; has antineoplastic activity | benzamides; monochlorobenzenes; pyridines; sulfone | antineoplastic agent; Hedgehog signaling pathway inhibitor; SMO receptor antagonist; teratogenic agent |
| N-[[3-fluoro-4-[[2-(1-methyl-4-imidazolyl)-7-thieno[3,2-b]pyridinyl]oxy]anilino]-sulfanylidenemethyl]-2-phenylacetamide | thioureas | ||
| ipi-926 | IPI-926: a semisynthetic derivative of cyclopamine that is a smoothened inhibitor with antineoplastic activity; structure in first source | piperidines | |
| gsk 1363089 | GSK 1363089: a multikinase inhibitor that acts on Met, RON, Axl, and VEGFR; structure in first source | aromatic ether | |
| tak-441 | TAK-441: structure in first source | ||
| ly2940680 | |||
| 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(6-(4-(4-ethylpiperazin-1-yl)-phenylamino)pyrimidin-4-yl)-1-methylurea | BGJ-398 : A member of the class of phenylureas that is urea in which a hydrogen attached to one of the nitrogens is replaced by a 2,6-dichloro-3,5-dimethoxyphenyl group, while the hydrogens attached to the other nitrogen are replaced by a methyl group and a 6-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl group. It is a potent and selective fibroblast growth factor receptor inhibitor. infigratinib: structure in first source | aminopyrimidine; dichlorobenzene; N-alkylpiperazine; N-arylpiperazine; phenylureas | antineoplastic agent; fibroblast growth factor receptor antagonist |
| cep-32496 | agerafenib: inhibitor of RAF family kinases; structure in first source | ||
| pf-5274857 | 1-(4-(5'-chloro-3,5-dimethyl-2,4'-bipyridin-2'-yl)piperazin-1-yl)-3-(methylsulfonyl)propan-1-one: a potent and selective Smoothened antagonist that penetrates the blood-brain barrier; structure in first source |