Common Partner Smad-Independent Canonical Bone Morphogenetic Protein Signaling in the Specification Process of the Anterior Rhombic Lip during Cerebellum Development

Abstract

Bone morphogenetic protein (BMP) signaling is critical for cerebellum development. However, the details of receptor regulatedSmad (R-Smad) and common partner Smad (Co-Smad, or Smad4) involvement are unclear. Here, we report that cerebellumspecific double conditional inactivation of Smad1 and Smad5 (Smad1/5) results in cerebellar hypoplasia, reduced granule cell numbers, and disorganized Purkinje neuron migration during embryonic development. However, single conditional inactivation of either Smad1 or Smad5 did not result in cerebellar abnormalities. Surprisingly, conditional inactivation of Smad4, which is considered to be the central mediator of canonical BMP-Smad signaling, resulted only in very mild cerebellar defects. Conditional inactivation of Smad1/5 led to developmental defects in the anterior rhombic lip (ARL), as shown by reduced cell proliferation and loss of Pax6 and Atoh1 expression. These defects subsequently caused the loss of the nuclear transitory zone and a region of the deep cerebellar nuclei. The normal maturation of the remaining granule cell precursors in the external granular layer (EGL) suggests Smad1/5 signaling is required for the specification process in ARL but not for the subsequent EGL development. Our results demonstrate functional redundancy for Smad1 and Smad5 but functional discrepancy between Smad1/5 and Smad4 during cerebellum development.

An Atypical Canonical Bone Morphogenetic Protein (BMP) Signaling Pathway Regulates Msh Homeobox 1 (Msx1) Expression during Odontogenesis

“…However, in other cellular processes that have high levels of BMP signaling, abundant phosphorylated R-Smads can be formed. Under these conditions, R-Smads can still activate their downstream targets, and Smad4 appears to be less important (10). This might explain why pSmad1/5/8 is able to function without Smad4 during early tooth development, in which high expression level of BMP4 is evident in the dental mesenchyme (44).…”

“…During nervous system development, conditional inactivation of Smad1 and Smad5 resulted in cerebellar hypoplasia, reduced granule cell numbers, and disorganized Purkinje neuron migration during embryonic development, whereas conditional inactivation of Smad4 produced only very mild cerebellar defects (10). Furthermore, during lens development, cell death occurred associated with inactivation of Smad1/5, but not with inactivation of Smad4 (12).…”

“…Although Smad4 is regarded the central mediator of the canonical BMP signaling pathway, it has been reported that phospho-(p)Smad1/5 are able to accumulate in the nucleus and transduce BMP signaling independently of Smad4 to the downstream target genes (9,10). In addition, in the development of several organs, including the nervous system, lens, and bone, inactivation of Smad1/5 causes severe defects, but Smad4 inactivation gives rise to no or mild defects (10 -13).…”

Development of the cerebellum: simple steps to make a ‘little brain’

“…roof plate (Alder et al, 1999;Fernandes et al, 2012;Tong and Kwan, 2013). Although this might suggest that the rhombic lip is a dorsally allocated progenitor pool, it is perhaps more appropriate to consider it as a zone of dynamic induction at the edge of the ventricular zone.…”

“…BMP signalling result in cerebellar defects (Fernandes et al, 2012;Tong and Kwan, 2013), although the interpretation of such experiments is confounded by earlier roles for BMP signalling during dorsal neural tube patterning (Alder et al, 1999;Lee and Jessell, 1999;Broom et al, 2012).…”