Subclass‐specific expression patterns of MET receptor tyrosine kinase during development in medial prefrontal and visual cortices

Abstract

Met encodes a receptor tyrosine kinase (MET) that is expressed during development and regulates cortical synapse maturation. Conditional deletion of Met in the nervous system during embryonic development leads to deficits in adult contextual fear learning, a medial prefrontal cortex (mPFC)‐dependent cognitive task. MET also regulates the timing of critical period plasticity for ocular dominance in primary visual cortex (V1). However, the underlying circuitry responsible remains unknown. Therefore, this study determines the broad expression patterns of MET throughout postnatal development in mPFC and V1 projection neurons (PNs), providing insight into similarities and differences in the neuronal subtypes and temporal patterns of MET expression between cortical areas. Using a transgenic mouse line that expresses green fluorescent protein (GFP) in Met+ neurons, immunofluorescence and confocal microscopy were performed to visualize MET‐GFP+ cell bodies and PN subclass‐specific protein markers. Analyses reveal that the MET expression is highly enriched in infragranular layers of mPFC, but in supragranular layers of V1. Interestingly, temporal regulation of the percentage of MET+ neurons across development not only differs between cortical regions but also is distinct between lamina within a cortical region. Further, MET is expressed predominantly in the subcerebral PN subclass in mPFC, but the intratelencephalic PN subclass in V1. The data suggest that MET signaling influences the development of distinct circuits in mPFC and V1 that underlie subcerebral and intracortical functional deficits following Met deletion, respectively.

Developmental and molecular contributions to contextual fear memory emergence in mice

“…mPFC contributes to contextual fear memory circuitry [ 39 , 40 ], and MET is enriched in subcerebral projection neurons in infragranular layers of mPFC throughout postnatal development in mice [ 41 ]. We hypothesized that age-dependent differences in the MET population could contribute to the observed female adult-specific deficit in fear memory.…”

Developmental and molecular contributions to contextual fear memory emergence in mice

“…Together, these data demonstrate adult-specific deficits in contextual fear memory following elimination of Met in neural cells. mPFC contributes to contextual fear memory circuitry [37][38], and MET is enriched in subcerebral projection neurons in infragranular layers of mPFC throughout postnatal development in mice [39]. We hypothesized that age-dependent differences in the MET population could contribute to the observed adult-specific deficit in fear memory.…”

Characterization of Gene Regulatory Elements in Human Fetal Cortical Development: Enhancing Our Understanding of Neurodevelopmental Disorders and Evolution

“…On the other hand, the same developmental genes are regulated differently in different areas. For example, DARP-32 is a marker of cortical-thalamic neurons in medial prefrontal cortex (mPFC) [39], but not visual cortex [40]. C-Met is enriched in layer 2-3 IT neurons in all sensory cortical regions, but not expressed in layer 2-3 neurons in mPFC; the receptor is expressed in corticothalamic neurons in mPFC, but not in primary sensory cortical regions [40].…”

“…For example, DARP-32 is a marker of cortical-thalamic neurons in medial prefrontal cortex (mPFC) [39], but not visual cortex [40]. C-Met is enriched in layer 2-3 IT neurons in all sensory cortical regions, but not expressed in layer 2-3 neurons in mPFC; the receptor is expressed in corticothalamic neurons in mPFC, but not in primary sensory cortical regions [40]. An interesting question is how to trace brain arealization at later stages, such as differences between prefrontal cortex and V1, back to these early events driven by developmental signaling pathways, so that we can generate better area-specific in vitro models.…”