Celf4 controls mRNA translation underlying synaptic development in the prenatal mammalian neocortex

Abstract

Abnormalities in neocortical and synaptic development are linked to neurodevelopmental disorders. However, the molecular and cellular mechanisms governing initial synapse formation in the prenatal neocortex remain poorly understood. Using polysome profiling coupled with snRNAseq on human cortical samples at various fetal phases, we identify human mRNAs, including those encoding synaptic proteins, with finely controlled translation in distinct cell populations of developing frontal neocortices. Examination of murine and human neocortex reveals that the RNA binding protein and translational regulator, CELF4, is expressed in compartments enriched in initial synaptogenesis: the marginal zone and the subplate. We also find that Celf4/CELF4-target mRNAs are encoded by risk genes for adverse neurodevelopmental outcomes translating into synaptic proteins. Surprisingly, deleting Celf4 in the forebrain disrupts the balance of subplate synapses in a sex-specific fashion. This highlights the significance of RNA binding proteins and mRNA translation in evolutionarily advanced synaptic development, potentially contributing to sex differences.

Cortical arealization of interneurons defines shared and distinct molecular programs in developing human and macaque brains

“…5b), we noticed MEIS2 PAX6 SCGN and MEIS2 FOXP2 TSHZ1 cells were reliably detected after GW18 in FC and MSC, whereas they could be detected as early as GW13 in GE, implying that the necessary accumulation was required before cells could initiate cortical migration. Moreover, the matched result was observed through re-analyzing the recently published snRNA-seq dataset of human neocortices during early fetal (11/12 PCW), early midfetal (14/15 PCW) and late mid-fetal (17/18 PCW) 71 , con rming the presence of MEIS2 SP8 SCGN cells in CTX during late mid-fetal stage (Supplementary Fig. 8a).…”

Chronic exposure to glucocorticoids amplifies inhibitory neuron cell fate during human neurodevelopment in organoids

“…In particular, some genes with a large fold-change in expression after exposure to GCs and a high correlation with the inhibitory neuron lineage were direct or second-order targets of PBX3 in the GRN of organoids exposed to GC. Examples included CELF4, a gene associated with synaptic development 43 , depression-like behavior in mice 44 , and ASD 45 . Another example was SYNPR, a common inhibitory neuron marker gene 46,47 (Fig.…”

Genetic architecture of the structural connectome

“…The eighth-most significant variant, rs4799450 (chr18:35,028,901), is an intronic variant in CELF4 . CELF4 is an RNA binding protein and translational regulator of prenatal neocortical subplate layer-based synaptic development 97 . CELF4 is involved in differentiation and excitation of neurons, corticothalamic development, synaptic transmission, and neuroplasticity and is an important regulator of mRNA stability and translational availability 98 .…”