BMP signaling patterns the dorsal and intermediate neural tube via regulation of homeobox and helix-loop-helix transcription factors

Abstract

In the spinal neural tube, populations of neuronal precursors that express a unique combination of transcription factors give rise to specific classes of neurons at precise locations along the dorsoventral axis. Understanding the patterning mechanisms that generate restricted gene expression along the dorsoventral axis is therefore crucial to understanding the creation of diverse neural cell types. Bone morphogenetic proteins (BMPs) and other transforming growth factor β (TGFβ) proteins are expressed by the dorsal-most cells of the neural tube (the roofplate) and surrounding tissues, and evidence indicates that they play a role in assigning cell identity. We have manipulated the level of BMP signaling in the chicken neural tube to show that BMPs provide patterning information to both dorsal and intermediate cells. BMP regulation of the expression boundaries of the homeobox proteins Pax6, Dbx2 and Msx1 generates precursor populations with distinct developmental potentials. Within the resulting populations, thresholds of BMP act to set expression domain boundaries of developmental regulators of the homeobox and basic helix-loop-helix (bHLH) families, ultimately leading to the generation of a diversity of differentiated neural cell types. This evidence strongly suggests that BMPs are the key regulators of dorsal cell identity in the spinal neural tube.

Beyond AOPs: A Mechanistic Evaluation of NAMs in DART Testing

“…Their expression is closely linked to extension of anterio-posterior body axis and controlled by signalling pathways such a Wnt, Fgf, and RA, as well as the Cdx transcription factors ( Dubrulle et al, 2001 ; van den Akker et al, 2002 ; Aulehla et al, 2003 ; Moreno and Kintner, 2004 ). Similarly, BMP signalling has been shown to pattern the spinal neural tube by regulating Hox transcription factors and the roles of BMP, Shh, Fgf, TSH, IGF1 and TGFβ are well recognized in regulating the thyroid transcription factors, including the Hox TFs, Nkx2-1and Hhex ( Timmer et al, 2002 ; Lopez-Marquez et al, 2021 ). Since the Hox genes are tightly and combinatorially regulated by growth factor signalling in a tissue specific manner, these upstream activating pathways may provide a better indication of regulation or perturbation of regulation in embryonic development.…”

Completion of neural crest cell production and emigration is regulated by retinoic acid-dependent inhibition of BMP signaling

“…In addition, gain and loss of Notch function in avians and mice, respectively, resulted in changes in RP formation with no apparent effects on NC cell behavior (Ofek et al, 2021). This would indicate that although NC and RP lineages arise from common progenitors (Bronner-Fraser and Fraser, 1988; Nitzan et al, 2012) by different exposure times and/or levels of BMP signaling (Nitzan et al, 2016; Timmer et al, 2002; Tozer et al, 2013), they segregate rather early from each other.…”

“…In addition, since dI1 interneurons are also specified by BMP signaling (Chesnutt et al, 2004; Hegarty et al, 2013; Timmer et al, 2002), it is conceivable to speculate that maintenance of BMP responsiveness in the RP of RARα403-treated NTs affects the normal dorso-ventral gradient of BMP activity (Tozer et al, 2013), perhaps eliciting indirectly an attractive function that enables dI1 interneurons to migrate into the RP domain. In this context, RP-derived BMP exhibits at a later stage chemorepellent properties vis-à-vis commissural axons (Augsburger et al, 1999; Butler and Dodd, 2003), putting forward the additional possibility of guidance functions for this morphogen under the present experimental conditions.…”

Cilia and their role in neural tube development and defects

“…During neurulation, the neural tube is formed from the neuroepithelium under the guidance of morphogens. Along the dorsal-ventral axis of the neural tube, the cell fates are mainly induced by SHH and bone morphogenetic proteins (BMPs) [11] . SHH is secreted from the notochord and floor plate cells on the ventral side, whereas BMPs are secreted from the epithelia and roof plate cells on the dorsal side.…”