Tgfβ Signaling Regulates Temporal Neurogenesis and Potency of Neural Stem Cells in the CNS

Abstract

How the sequential specification of neurons and progressive loss of potency associated with aging neural progenitors are regulated in vertebrate brain development is poorly understood. By examining a temporal differentiation lineage in the hindbrain, we here identify Tgfβ as a switch signal that executes the transition between early and late phases of neurogenesis and concurrently constrains progenitor potency. Young progenitors have inherent competence to produce late-born neurons, but implementation of late-differentiation programs requires suppression of early identity genes achieved through temporally programmed activation of Tgfβ downstream of Shh signaling. Unexpectedly, we find that sequentially occurring fate-switch decisions are temporally coupled, and onset of Tgfβ signaling appears thereby to impact on the overall lifespan of the temporal lineage. Our study establishes Tgfβ as a regulator of temporal identity and potency of neural stem cells, and provides proof of concept that Tgfβ can be applied to modulate temporal specification of neurons in stem cell engineering.

Playing Well with Others: Extrinsic Cues Regulate Neural Progenitor Temporal Identity to Generate Neuronal Diversity

“…Second, ablation of early-born deep layer neurons leads to prolonged early-born neuron production and a delay in generating late-born upper layer neurons, suggesting a negative feedback signal from early-born neurons to ventricular zone progenitors [16]. Third, TGFβ signaling is required in three different brain regions to trigger a switch from early-born to late-born neural subtypes [17]. Fourth, the Wnt7 ligand provides a feedback signal from newly-born neurons to cortical progenitors to trigger a switch from neurogenesis to gliogenesis [18].…”

Developmental Pattern Formation in Phases

“…Shh-dependent changes in the expression of Forkhead box A2 (FoxA2), a Phox2B repressor, have previously been correlated with the switch [63]. More recently, transforming growth factor b2 (TGFb2) was identified as a locally acting repressor of Phox2B [64]. Delayed induction of TGFb2 in the vMN domain and the subsequent dynamics of Phox2B repression are proposed to determine the duration of the vMN generation phase [64].…”

“…More recently, transforming growth factor b2 (TGFb2) was identified as a locally acting repressor of Phox2B [64]. Delayed induction of TGFb2 in the vMN domain and the subsequent dynamics of Phox2B repression are proposed to determine the duration of the vMN generation phase [64]. An intriguing possibility is that the ability of TGFb2 to diffuse may be used in this system to orchestrate the coordinated transition of all progenitors to a new state.…”

Opportunities lost and gained: Changes in progenitor competence during nervous system development

“…57 More recently, Dias et al identified TGFb signaling as a temporally regulated cue that downregulates Phox2b expression; reduced TGFb signaling delayed the MN-to-5HTN switch, altering the number of neurons in each population. 58 This system illustrates how temporal regulation of cell fate determinates (e.g., Phox2b) can subdivide a single competence window to generate neuronal diversity, and how an extrinsic cue can determine the timing of the switch between neuronal cell types.…”