Revisiting the expression of BDNF and its receptors in mammalian development

Abstract

Brain-derived neurotrophic factor (BDNF) promotes the survival and functioning of neurons in the central nervous system and contributes to proper functioning of many non-neural tissues. Although the regulation and role of BDNF have been extensively studied, a rigorous analysis of the expression dynamics of BDNF and its receptors TrkB and p75NTR is lacking. Here, we have analyzed more than 3,600 samples from 18 published RNA sequencing datasets, and used over 17,000 samples from GTEx, and ~ 180 samples from BrainSpan database, to describe the expression of BDNF in the developing mammalian neural and non-neural tissues. We show evolutionarily conserved dynamics and expression patterns of BDNF mRNA and non-conserved alternative 5′ exon usage. Finally, we also show increasing BDNF protein levels during murine brain development and BDNF protein expression in several non-neural tissues. In parallel, we describe the spatiotemporal expression pattern of BDNF receptors TrkB and p75NTR in both murines and humans. Collectively, our in-depth analysis of the expression of BDNF and its receptors gives insight into the regulation and signaling of BDNF in the whole organism throughout life.

An 840 kb distant upstream enhancer is a crucial regulator of catecholamine‐dependent expression of the Bdnf gene in astrocytes

“…The multi‐promoter composition of Bdnf gene allows generating alternative Bdnf transcripts, which result in identical BDNF protein. This kind of gene regulation ensures complex spatiotemporal expression of BDNF (Esvald et al, 2023 ; West et al, 2014 ). For instance, the first cluster of Bdnf transcripts is expressed in neurons, but not in non‐neuronal cells, and, in contrast, the second cluster of Bdnf transcripts is expressed ubiquitously in both neuronal and non‐neuronal tissues (Aid et al, 2007 ; Esvald et al, 2023 ; Pruunsild et al, 2007 ; Timmusk et al, 1993 ).…”

“…This kind of gene regulation ensures complex spatiotemporal expression of BDNF (Esvald et al, 2023 ; West et al, 2014 ). For instance, the first cluster of Bdnf transcripts is expressed in neurons, but not in non‐neuronal cells, and, in contrast, the second cluster of Bdnf transcripts is expressed ubiquitously in both neuronal and non‐neuronal tissues (Aid et al, 2007 ; Esvald et al, 2023 ; Pruunsild et al, 2007 ; Timmusk et al, 1993 ). Likely, this spatiotemporal regulation is maintained by both cell type‐specific activity of proximal promoters (Palm et al, 1999 ; Zuccato et al, 2003 ) and recruitment of specific enhancer regions (Brookes et al, 2023 ; Flavell et al, 2008 ; Lyons et al, 2012 ; Tuvikene et al, 2021 ).…”

“…However, we acknowledge that our CAPTURE‐3C‐sequencing might lack the resolution and statistical power to detect the possible short‐range interactions within the Bdnf locus. We have previously shown that Bdnf is regulated as two clusters of promoters (Aid et al, 2007 ; Esvald et al, 2023 ; Pruunsild et al, 2007 ; Timmusk et al, 1993 ), and that the intronic enhancer located downstream of exon III is responsible for neuron‐specific expression of the first cluster of Bdnf exons (Tuvikene et al, 2021 ). It is plausible that the enhancers of Bdnf loop together with the anchor point located nearby the first, second, or both of the clusters depending on the cell type and stimulus.…”

Associations of BDNF/BDNF-AS SNPs with Depression, Schizophrenia, and Bipolar Disorder

“…The alteration of BDNF levels, as well as the imbalance between pro-BDNF and m-BDNF, and deficits in BDNF signaling are associated with the pathogenesis of various neurologic and psychiatric disorders, including depressive disorder, schizophrenia, and bipolar disorder [ 8 , 11 , 23 , 38 , 39 , 40 , 41 ].…”

NRN1 epistasis with BDNF and CACNA1C: mediation effects on symptom severity through neuroanatomical changes in schizophrenia

“…Additionally, it has been described that another neuropeptide, the Brain-Derived Neurotrophic Factor (BDNF, 11p13), modulates NRN1 expression. This gene is highly expressed in the same cerebral regions as NRN1 (Esvald et al 2023) and also in an experience-dependent manner (Tongiorgi 2008). As neurotrophins, both genes exert multiple functions in the developing brain, being involved, for example, in enhancing neurite and dendritic growth, stabilising active synapses, improving synaptic maturation, increasing neuronal migration and regulating apoptosis of proliferative neurons, but are also involved in regulating the neuronal plasticity in the adult brain (Sasi et al 2017;Yao et al 2018).…”