FGF signalling generates ventral telencephalic cells independently of SHH

Gutin, Grigoriy; Fernandes, Marie; Palazzolo, Laura; Paek, Hun Ki; Yu, Kai; Ornitz, David M.; McConnell, Susan K.; Hébert, Jean M.

doi:10.1242/dev.02465

Cited by 135 publications

(137 citation statements)

References 65 publications

Supporting

Mentioning

128

Contrasting

Unclassified

Order By: Relevance

“…Therefore, we propose that Six3 regulation of Foxg1 mediates dorsoventral patterning of the telencephalon in an Shh-independent pathway. The Fgf signaling pathway has also been suggested to promote ventral telencephalic specification independently of Shh (Gutin et al, 2006). Mutations in FGF8 and FGFR1 have been identified in human patients with HPE (McCabe et al, 2011;Simonis et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Six3 dosage mediates the pathogenesis of holoprosencephaly

et al. 2016

View full text Add to dashboard Cite

Holoprosencephaly (HPE) is defined as the incomplete separation of the two cerebral hemispheres. The pathology of HPE is variable and, based on the severity of the defect, HPE is divided into alobar, semilobar, and lobar. Using a novel hypomorphic Six3 allele, we demonstrate in mice that variability in Six3 dosage results in different HPE phenotypes. Furthermore, we show that whereas the semilobar phenotype results from severe downregulation of Shh expression in the rostral diencephalon ventral midline, the alobar phenotype is caused by downregulation of Foxg1 expression in the anterior neural ectoderm. Consistent with these results, in vivo activation of the Shh signaling pathway rescued the semilobar phenotype but not the alobar phenotype. Our findings show that variations in Six3 dosage result in different forms of HPE.

show abstract

Section: Discussionmentioning

confidence: 99%

Six3 dosage mediates the pathogenesis of holoprosencephaly

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Shh is dispensable for induction of the BMP/Wnt-expressing dorsal midline, as, perhaps, is Fgf8, previously suggested to mediate dorsal midline induction by Shh. Expression of multiple Fgf genes, including Fgf8, is severely reduced in the Shh mutant; moreover, mouse lines engineered for defective Fgf signaling can develop a dorsal telencephalic midline (Garel et al, 2003;Gutin et al, 2006;Storm et al, 2006). Juxtaposed sources of Shh, Fgf8, and BMP/Wnt proteins regulate one another to pattern the telencephalon (Crossley et al, 2001;Ohkubo et al, 2002;Shimogori et al, 2004) but are not the only patterning cues.…”

Section: Discussionmentioning

confidence: 99%

Patterning the Dorsal Telencephalon: A Role for Sonic Hedgehog?

Rash¹,

Grove²

2007

J. Neurosci.

View full text Add to dashboard Cite

Division of the telencephalic vesicle into hemispheres and specification of the cerebral cortex are key stages in forebrain development. We investigate the interplay in these processes of Sonic hedgehog (Shh), fibroblast growth factors (Fgfs), and the transcription factor Gli3, which in its repressor form (Gli3R) antagonizes Shh signaling and downregulates expression of several Fgf genes.Contrary to previous reports, Shh is not required for dorsal hemisphere separation. Mice lacking Shh develop a dorsal telencephalic midline, a cortical hem, and two cortical hemispheres. The hemispheres do not divide rostrally, probably because of reduced local Fgf gene expression, resulting from the loss of Shh inhibition of Gli3R. Removing one functional copy of Gli3 substantially rescues Fgf expression and rostral telencephalic morphology.In mice lacking Gli3 function, cortical development is arrested, and ventral gene expression invades the dorsal telencephalon. These defects are potentially explained by disinhibition of Shh activity. However, when both copies of Shh are removed from Gli3-null mice, dorsal telencephalic defects persist. One such defect is a large dorsal expansion of the expression of Fgf genes. Fgf15 expression, for example, expands from a discrete ventral domain throughout the dorsal telencephalon. We propose that Fgf signaling, known to ventralize the telencephalon in a Shh-independent manner, suppresses cortical fate in the absence of Gli3. Our findings point away from Shh involvement in dorsal telencephalic patterning and encourage additional exploration of Fgf signaling and Gli3 repression in corticogenesis.

show abstract

“…Alternatively, Gli3 might be required to maintain dorsal-medial r1 identity, and the expansion of Fgf8 expression is a secondary consequence of a mixed r1/isthmus identity. Interestingly, a similar interaction between Shh, Gli3 and Fgf8 exists in the developing telencephalon (Gutin et al, 2006;Kuschel et al, 2003;Ohkubo et al, 2002), suggesting that the interplay between these two signaling pathways constitutes a more general mechanism in the patterning of three-dimensional brain structures.…”

Section: Gli3r Is Required To Restrict Fgf8 Expression To the Isthmusmentioning

confidence: 97%

Gli3 coordinates three-dimensional patterning and growth of the tectum and cerebellum by integrating Shh and Fgf8 signaling

2008

View full text Add to dashboard Cite

The coordination of anterior-posterior (AP) and dorsal-ventral (DV) patterning of the mesencephalon (mes) and rhombomere 1 (r1) is instrumental for the development of three distinct brain structures: the tectum and cerebellum dorsally and the tegmentum ventrally. Patterning of the mes/r1 is primarily mediated by signaling molecules secreted from two organizers: sonic hedgehog (Shh) from the floor plate (DV) and Fgf8 from the isthmus (AP). Gli3, a zinc-finger transcription factor in the Shh signaling pathway, has been implicated in regulating Fgf8 expression and is therefore a potential candidate for coordinating the action of the two organizers. By inactivating mouse Gli3 at successive embryonic time points in vivo, we uncovered the extent and the underlying mechanism of Gli3 function in the mes/r1. We demonstrate that before E9.0, Gli3 is required for establishing a distinct posterior tectum, isthmus and cerebellum, but does not play a role in the development of the tegmentum. Between E9.0 and E11.0, Gli3 continues to be required for isthmus and cerebellum development, but primarily for defining the cerebellar foliation pattern. We show that Gli3 regulates patterning of the isthmus and cerebellar anlage by confining Fgf8 expression to the isthmus, and attenuates growth of dorsal r1 (before E11.0) and the dorsal mes and isthmus (beyond E11.0) through regulation of cell proliferation and viability. In conclusion, our results show that Gli3 is essential for the coordinated three-dimensional patterning and growth of the dorsal mes/r1. KEY WORDS: Anterior-posterior patterning, Dorsal-ventral patterning, Isthmic organizer, Mid/hindbrain, Mouse

show abstract

FGF signalling generates ventral telencephalic cells independently of SHH

Cited by 135 publications

References 65 publications

Six3 dosage mediates the pathogenesis of holoprosencephaly

Six3 dosage mediates the pathogenesis of holoprosencephaly

Patterning the Dorsal Telencephalon: A Role for Sonic Hedgehog?

Gli3 coordinates three-dimensional patterning and growth of the tectum and cerebellum by integrating Shh and Fgf8 signaling

Contact Info

Product

Resources

About