Table 1.
Morphogenetic pathways involved in endoderm induction and specification of thyroid primordium.
| Signaling Pathwav | Gene | Experimental condition | Endoderm and/or Thyroid phenotypes | References |
|---|---|---|---|---|
| Nodal | oep | Mutant fish line (oeptz57) | Failure of mesendodermal cells commitment, loss of endoderm specification, absence of thyroid primordium | (59, 60) |
| cyc | Mutant fish line (cycm294) | Incomplete development of pharyngeal endoderm, reduced number of functional thyroid follicles | (59, 61) | |
| cyc, hhex | Mutant fish line (cycmb16) | Absence specification of thyroid primordium, no functional thyroid follicles | (59, 63) | |
| sox32 | Mutant fish line (casta56) | Lack of endodermal precursors | (59, 63) | |
| bon | Mutant fish line (bons9) | Reduced number of endodermal precursors, absence of gut tube | (59, 63) | |
| gata5 | Mutant fish line (faus26) | Reduced number of endodermal precursors | (57, 59) | |
| tgf-β | LY364947 and SB505124 inhibitors | Alteration of anterior endoderm, slight reduction of thyroid progenitors | (9) | |
| Notch | notch-NICD | Conditional KI fish line [late somitogenesis] | Reduced thyroid primordium specification, low number of functional follicles | (77) |
| mib | Mutant fish line (Mibta52b) | Increased thyroid primordium specification, increased number of functional follicles | (77) | |
| jagla, jalb | Morphilino-mediated KD, Mutant fish line (jag1bb1005) | Jagla: reduced proliferation of differentiated follicles; jaglb: reduced thyroid promordium specification | (77) | |
| γ-secretase | DAPT inhibitor [gastrula] | Increased thyroid primordium specification, increase number of functional follicles | (77) | |
| γ-secretase | LY411575, RO4929097 inhibitors [gastrula, somitogenesis] | No significant abnormality detected | (9) | |
| Sonic Hedgehog | shh | Morpholino-mediated KD | Abnormal thyroid migration | (8) |
| glis3 | Morpholino-mediated KD | Reduced thyroid primordium specification, low number of functional follicles | (83) | |
| ptch1 | Cyclopamine inhibitor [gastrula] | Reduced thyroid primordium specification | (83) | |
| ptch1 | Cyclopamine inhibitor [gastrula, somitogenesis] | Slight impairment of follicle migration | (9) | |
| smo | Purmophamine, SAG inhibitors [gastrula, somitogenesis] | No significant abnormality deteted | (9) | |
| FGF | fgf8 | Morpholino-mediated KD, Mutant fish line (aceti282a) | Increased number of endodermal precursors, reduced expression of TTFs, loss of functional follicles | (56, 93) |
| hand2 | Mutant fish lines (hans6, hanc99) | Reduced or absent expression of thyroid markers, loss of fuctional follicles | (93, 94) | |
| fgfr 1 | SU5402, PD166866 inhibitor [gastrula, somitogenesis] | Gastrula: increased thyroid primordium specification; somitogenesis: no thyroid primordium specification | (9) | |
| fgfr 1 | PD166866 inhibitor [early, middle, and late somitogenesis] | No significant changes detected in TTFs expression | (16) | |
| fgfr 1 | Conditonal KI fish line [early, middle, and late somitogenesis] | Middle/late: increment of thyroid progenitors that express pax2a | (16) | |
| BMP | bmp2b | mRNA injection | No consequence of number of endoderm precursors | (98) |
| bmp2b, bmp4, bmp7 | mRNA injection | Reduction of endodermal precursors number | (56) | |
| noggin | mRNA injection | Slight increase of endodermal precursors number | (56) | |
| alk2, and alk1-3 and 6 | DMH1, LDN193189 inhibitors [gastrula, somitogenesis] | Gastrula: altered specification of thyroid bud; somitogenesis: no thyroid primordium specification | (9) | |
| alk2 | DMH1 inhibitor [early, middle, and late somitogenesis] | Early: absence of thyroid progenitors; middle: mild reduction of TFFs expression; late dramatic reduction of TFFs in thyroid primordium: | (16) | |
| bmp2b | Conditional KI fish line [early, middle, and late somitogenesis] | Early: increment of nkx2.4b+ precursors and thyroid enlargement that abnormally elongate along the AP axis; middle/late: enlargement of the pax2a+ thyroid precursor population and premature expression of nkx2.4b | (16) | |
| Wnt | gsk3a and gsk3β | BIO and AZA activators [gastrula, somitogenesis, thyroid anlage, folliculogenesis] | Gastrula/somitogenesis: severe alteration of endoderm specification; thyroid anlage/folliculogenesis: reduction of thyroid primordium | (9, 15) |
| FGF + BMP | fgf8, fgf17b, fgf24, and nogging | Morpholino-mediated KD (for FGF) and mRNA injection (for BMP) | Massive increment of endodermal precursors population | (56) |
For each signaling pathway, the gene (in italics), the experimental condition used to generate the zebrafish model, the associated endoderm and/or thyroid phenotype, and the corresponding references are reported. When available, the developmental stage selected to start the treatment with inhibitors are also reported in the squared parenthesis. AP axis, antero-posterior axis; KD, knockdown; KI, knockin; NICD, Notch Intracellular domain; TTFs, thyroid transcription factors.