Molecular underpinnings of prefrontal cortex development in rodents provide insights into the etiology of neurodevelopmental disorders

Abstract

The prefrontal cortex (PFC), seat of the highest-order cognitive functions, constitutes a conglomerate of highly specialized brain areas and has been implicated to have a role in the onset and installation of various neurodevelopmental disorders. The development of a properly functioning PFC is directed by transcription factors, guidance cues and other regulatory molecules and requires the intricate and temporal orchestration of a number of developmental processes. Disturbance or failure of any of these processes causing neurodevelopmental abnormalities within the PFC may contribute to several of the cognitive deficits seen in patients with neurodevelopmental disorders. In this review, we elaborate on the specific processes underlying prefrontal development, such as induction and patterning of the prefrontal area, proliferation, migration and axonal guidance of medial prefrontal progenitors, and their eventual efferent and afferent connections. We furthermore integrate for the first time the available knowledge from genome-wide studies that have revealed genes linked to neurodevelopmental disorders with experimental molecular evidence in rodents. The integrated data suggest that the pathogenic variants in the neurodevelopmental disorder-associated genes induce prefrontal cytoarchitectonical impairments. This enhances our understanding of the molecular mechanisms of prefrontal (mis)development underlying the four major neurodevelopmental disorders in humans, that is, intellectual disability, autism spectrum disorders, attention deficit hyperactivity disorder and schizophrenia, and may thus provide clues for the development of novel therapies.

Figure 1

Bird's eye view of developmental events required for prefrontal cortex (PFC) formation. The identity of the PFC is sculpted over time by intrinsic developmental mechanisms such as expansion by proliferation and regional specification by the differential expression of intrinsic factors (e.g., transcription factors), indicated in blue. These intrinsic factors can control genes (transcriptional control) that affect other developmental events such as the expression and release of soluble morphogens, migration of neurons or guidance molecules that direct axons from other brain areas towards the PFC and vice versa to establish appropriate connectivity. These extrinsic factors are depicted in red. Pruning of appropriate connections and neuron death are under the control of external stimuli (green).

Figure 2

Molecular stages in the development of the PFC. (a) Schematic representation of the frontal view of a young (E11.5) mouse forebrain showing inductive influences (morphogens such as Fgfs, Wnts, SHH and BMPs; stage I). (b) Sagittal schematic views. These morphogens (stage I) have an effect on regional specification through intrinsic expression of transcription factors (stage II). This combinatorial code will have its effect on the cell-type specification of the major neurotransmitter systems (stage III). The neurotransmitter systems will connect to the PFC, shaping it and establishing the respective neural networks (stage IV). ANR, anterior neural ridge; DA, dopaminergic; DI, diencephalon; MES, mesencephalon; MET, metencephalon; MHB, mid-hindbrain border; NA, noradrenergic; PFC, prefrontal cortex; RPC, rostral patterning center; SHH, sonic hedgehog; Tel, telencephalon; VSC, ventral signaling center; ZL, zona limitans; 5-HT, serotonergic.

Figure 3

Neurodevelopmental disorder-associated genes that are involved in mPFC development. Various genes are associated with neurodevelopmental events in the mPFC (proliferation, migration, guidance targeting and connectivity) of which some can also be found in association studies with the four major neurodevelopmental disorders ID, ASDs, AD(H)D, schizophrenia. The letter size in the ‘cloud' of genes is indicative of the frequency of the gene associated with the various neurodevelopmental disorders connected to that particular neurodevelopmental event. Cg, cingulate cortex; CP, cortical plate; DN, dividing neuroblast; GC, growth cone; IL, infralimbic cortex; IN, interneuron; IPC, intermediate progenitor; IZ, intermediate zone; MN, migrating neuron, PN, post-mitotic neuron; PrL, prelimbic cortex; PZ, proliverative zone; RG, radial glia; (1) Commissural and corticocortical projection neurons, respectively; (2) subcerebral projection neurons to basal ganglia, diencephalon, midbrain, hindbrain and spinal cord; (3) corticothalamic projection neurons to mediodorsal thalamic targets; (2) and (3)=corticofugal.