Bone Morphogenic Protein Signaling Regulates the Formation and Maturation of the External Granule Layer in the Developing Cerebellum

Core Concepts

BMP signaling is required for the initial assembly of the external granule layer (EGL) through the tangential migration of granule cell precursors, and subsequently regulates the tempo of granule cell maturation and differentiation within the EGL.

Abstract

The study examines the role of bone morphogenic protein (BMP) signaling during the development of the cerebellum, with a focus on its effects on the formation and maturation of the external granule layer (EGL). Key findings: In the chick cerebellum, BMP signaling, as indicated by phosphorylated Smad1/5/9 (pSmad) expression, is initially uniform throughout the forming EGL, but then decreases as the cerebellum begins to fold into folia. In contrast, in the human cerebellum, pSmad expression remains uniform across the EGL during foliation. Experimental manipulation of BMP signaling in the chick cerebellum reveals that BMP is required for the initial tangential migration of granule cell precursors from the rhombic lip to form the EGL. Inhibition of BMP signaling prevents the formation of the EGL, while upregulation of BMP signaling accelerates the maturation of granule cells, leading to a premature depletion of the EGL. The effects of altering BMP signaling are cell-autonomous, with BMP downregulation causing granule cells to bypass the EGL and directly differentiate, while BMP upregulation drives premature granule cell maturation and exit from the EGL. These findings suggest that the precise spatiotemporal regulation of BMP signaling is crucial for the proper assembly and maturation of the EGL, which in turn influences the overall development and foliation of the cerebellum. The differences observed between chick and human cerebella indicate an evolutionary adaptation of BMP signaling to support the protracted development of the human cerebellum.

Stats

"Granule cell precursors are born from the rhombic lip around embryonic day 6 (E6) in the chick, forming the EGL by E7." "In the chick, BMP activity is significantly higher in the EGL of the folia crests compared to the fissures (p= 0.0015)." "In the 19 pcw human cerebellum, the number of Purkinje cell soma per dorsal-ventral column is significantly lower at the folia crests compared to the troughs (p=0.0002)." "Upregulation of BMP signaling by Smad1EVE electroporation at E4 results in a 4-fold increase in EGL thickness between E7 and E8, correlating with a significant increase in mitotic marker (PH3) density (p<0.0001)."

Quotes

"Improper development of cerebellar granule neurons can manifest in a plethora of neurodevelopmental disorders, including but not limited to medulloblastoma and autism." "Granule cell production can be independent of the formation of an EGL." "Sustained BMP signalling within the EGL may play an important role in sustaining transit amplification over the protracted developmental time course of the human cerebellum."

Key Insights Distilled From

BMP signalling facilitates transit amplification in the developing chick and human cerebellum

by Rook,V., Hal... at www.biorxiv.org 10-12-2020

https://www.biorxiv.org/content/10.1101/2020.10.12.335612v3

Deeper Inquiries

How do the differences in BMP signaling dynamics between chick and human cerebella relate to the evolutionary adaptations that have led to the increased complexity and foliation of the human cerebellum?

The differences in BMP signaling dynamics between chick and human cerebella reflect the evolutionary adaptations that have occurred to accommodate the increased complexity and foliation of the human cerebellum. In the chick cerebellum, BMP signaling correlates with the formation of the external granule layer (EGL) during development. This suggests that BMP signaling plays a crucial role in the initial stages of granule cell neurogenesis and EGL assembly in avian species. However, in the human cerebellum, BMP signaling is maintained throughout the EGL even after the onset of foliation. This sustained BMP signaling in humans may contribute to the prolonged period of transit amplification and granule cell production, which is characteristic of the extended developmental timeline of the human cerebellum. The evolutionary adaptations that have led to the increased complexity and foliation of the human cerebellum may involve the regulation of BMP signaling to support the prolonged proliferation and differentiation of granule cells. The sustained BMP signaling in the human EGL could be a mechanism to maintain the balance between proliferation and differentiation over an extended period, allowing for the generation of a larger and more complex cerebellar structure. This adaptation may have provided evolutionary advantages in the development of higher cognitive functions and motor coordination in humans compared to other species.

How do the differences in BMP signaling dynamics between chick and human cerebella relate to the evolutionary adaptations that have led to the increased complexity and foliation of the human cerebellum?

The balance between granule cell proliferation and differentiation within the external granule layer (EGL) is finely tuned by the interaction of BMP signaling with other signaling pathways and transcriptional regulators. BMP signaling is known to antagonize Sonic hedgehog (Shh) signaling, which is essential for the proliferation of granule cell precursors in the EGL. The crosstalk between BMP and Shh pathways regulates the tempo of granule cell maturation and the transition from proliferative divisions to terminal differentiation in the EGL. In addition to Shh signaling, other signaling pathways such as Notch signaling and Wnt signaling may also interact with BMP signaling to modulate granule cell development in the cerebellum. Notch signaling is involved in the specification of rhombic lip derivatives, which give rise to granule cell precursors. The integration of BMP signaling with Notch signaling may influence the initial fate determination of granule cell progenitors at the rhombic lip. Wnt signaling, on the other hand, has been implicated in the regulation of cell proliferation and differentiation in various developmental contexts. The interplay between BMP, Shh, Notch, and Wnt signaling pathways likely coordinates the complex processes of granule cell neurogenesis in the cerebellum.

Could targeted modulation of BMP signaling be a potential therapeutic avenue for addressing neurodevelopmental disorders or brain tumors that originate from disruptions in cerebellar granule cell development?

Targeted modulation of BMP signaling holds promise as a potential therapeutic avenue for addressing neurodevelopmental disorders or brain tumors that arise from disruptions in cerebellar granule cell development. The findings from the study suggest that BMP signaling plays a critical role in regulating the balance between granule cell proliferation and differentiation within the EGL. Dysregulation of BMP signaling can lead to aberrant granule cell development, which is implicated in neurodevelopmental disorders such as medulloblastoma and autism. By manipulating BMP signaling levels, either through upregulation or downregulation, it may be possible to restore the normal balance of granule cell proliferation and differentiation in the cerebellum. For example, in conditions where BMP signaling is overactive, targeted inhibition of BMP pathways could potentially slow down the maturation of granule cells and prevent premature differentiation. Conversely, in cases where BMP signaling is deficient, targeted activation of BMP pathways could promote the proper proliferation and differentiation of granule cells. Overall, targeted modulation of BMP signaling offers a potential therapeutic strategy for correcting abnormalities in cerebellar granule cell development associated with neurodevelopmental disorders and brain tumors. Further research and preclinical studies are needed to explore the efficacy and safety of manipulating BMP signaling as a therapeutic intervention in these conditions.