The human-specific gene FRMPD2B couples postnatal experience to the expansion of cortical connectivity

E. Christopoulou; J. Zamith; P. Bonadonna; M. Rivero Romano; M. Vaudin; W. Nguyen; C. Brunet; C. Blugeon; S. Lemoine; F. Giudicelli; A. Baffet; C. Charrier

doi:10.64898/2026.10.30.763086

AI summary · DOI: 10.64898/2026.10.30.763086 · bioRxiv: Neuroscience

The human-specific gene FRMPD2B couples postnatal experience to the expansion of cortical connectivity

E. Christopoulou, J. Zamith, P. Bonadonna, M. Rivero Romano, M. Vaudin, W. Nguyen, C. Brunet, C. Blugeon,

and 4 more authors

S. Lemoine, F. Giudicelli, A. Baffet, C. Charrier

Original paper Published on 01 Nov. 2026 bioRxiv preprint License: CC BY-NC 4.0 Also in: fr

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The essentials

The paper identifies FRMPD2B as an experience- and activity-regulated human-specific gene that supports complex cortical neuron morphology and connectivity.

Question

The study asks whether human-specific genetic changes created activity-dependent mechanisms that shape postnatal cortical circuit development. It investigates FRMPD2B’s regulation, evolutionary origin, and role in cortical pyramidal neurons.

Method

The authors combined human cortical RNA sequencing and expression datasets with mouse in utero electroporation, promoter-reporter experiments, sensory deprivation and environmental enrichment, and xenotransplantation of human cortical neurons derived from pluripotent stem cells. They tested FRMPD2B and MEF2 knockdown in xenotransplanted neurons one month after transplantation, and compared human, ancestral-paralog, and macaque promoter sequences, including deletion of a MEF2-binding site.

Findings

Result FRMPD2B encodes a short protein and is expressed in human cortical neurons during a developmental period when dendrites and synaptic connections are forming.
See the passage in the paper
Using long-read nanopore sequencing, we found that it encodes a 320-amino-acid protein corresponding to the C-terminal part of FRMPD2A starting from the middle of the second PDZ domain (Fig. 1b).
Result In mouse upper-layer cortical pyramidal neurons, FRMPD2B increased basal dendritic branching and length, spine density, miniature excitatory postsynaptic current frequency, axonal branching, and presynaptic bouton density.
See the passage in the paper
In juvenile mice (postnatal day (P)21), FRMPD2B increased the branching and length of basal dendrites without modifying apical dendrites (Fig. 2c, d).
Result FRMPD2B promoter activity responded bidirectionally to experience and neuronal activity in mouse cortical neurons.
See the passage in the paper
At P14, the activity of pFRMPD2B in upper layer CPNs of the somatosensory cortex was lower in sensory-deprived mice than in their control littermates (Fig. 3c, d).
Authors’ interpretation The authors attribute the promoter’s experience responsiveness to a MEF2-binding site introduced by an AluYe5 insertion after the gene duplication.
See the passage in the paper
Deletion of the MEF2 binding site in pFRMPD2B abolished both the developmental increase in promoter activity and its experience-dependent regulation (Fig. 4e).
Result Knocking down FRMPD2B reduced dendritic length and branching in xenotransplanted human upper-layer cortical neurons, supporting its necessity for their complex morphology.
See the passage in the paper
Despite similar distance from the pial surface, as measured by the length of the main apical dendrite, human CPNs knocked down for FRMPD2B with two distinct shRNAs had a much simpler morphology, with less branched and shorter dendrites than control neurons (Fig. 5c, d and Fig. S7e).

Limitations

The human-neuron loss-of-function evidence comes from xenotransplanted cells assessed one month after transplantation, rather than from observations of human cortical development in vivo.
See the passage in the paper
EGFP-positive xenotransplanted human CPNs were imaged and analyzed 1 month post-transplantation (1 MPT).
The authors cannot exclude expression of short transcripts originating from the ancestral gene that cannot be distinguished from FRMPD2B transcripts.
See the passage in the paper
Although we cannot rule out that short transcripts originating from the ancestral gene, indistinguishable from FRMPD2B transcripts, are also expressed in the neocortex, the developmental and experience-dependent regulation is unique to FRMPD2B.
The authors do not establish whether FRMPD2B contributes to the pathophysiology of neurodevelopmental disorders.
See the passage in the paper
Determining whether and how human-specific modifiers of neuronal and synaptic development impact these disorders, and deciphering the human-specific aspects of their pathophysiology will be critical for future therapeutic strategies.

Why it matters

The authors argue that FRMPD2B reveals an evolutionary route to expanded cortical connectivity in which human-specific genetic changes link postnatal experience to neuronal development. Their work also provides an experimental approach for studying late-born, upper-layer human cortical neurons through xenotransplantation.

Written by AI from the paper. Passages are checked word for word against the text we analysed; the rest may contain errors.

AI-generated keywords: FRMPD2B cortical development neuronal activity postnatal experience human-specific gene duplication

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Comprehensive Summary
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Original abstract

The paper investigates whether a human-specific genetic innovation helps explain how postnatal experience shapes cortical connectivity. It focuses on FRMPD2B, a gene created by partial duplication of the ancestral FRMPD2A gene approximately 2.3 million years ago. The authors examine when and where FRMPD2B is expressed, whether neuronal activity and experience regulate it, how it affects neuronal development, and how its regulation evolved. Using long-read RNA sequencing and published expression datasets, the authors found that FRMPD2B produces a short protein of 320 amino acids. They did not detect long FRMPD2A transcripts in the human cortex. FRMPD2 expression was concentrated in excitatory neurons involved in cortico-cortical projections. In humans, expression began in late gestation, peaked between one and two years after birth, remained elevated through childhood, and declined in adulthood. Comparable expression was barely detectable in macaque cortex. To test FRMPD2B’s effects, the researchers used in utero electroporation to express it in upper-layer cortical pyramidal neurons in mouse brains. By postnatal day 21, FRMPD2B had increased basal dendrite length and branching, but had not measurably changed apical dendrites. It also increased dendritic spine density and presynaptic bouton density in cortical layers 2/3 and 5. At postnatal days 17–19, miniature excitatory postsynaptic current frequency was higher, while current amplitude and intrinsic membrane properties were unchanged. Axonal branching also increased at postnatal days 6 and 21. Together, these results suggest that FRMPD2B can promote several aspects of neuronal growth and synaptic connectivity in this mouse overexpression model. The team next tested whether FRMPD2B promoter activity responds to development, experience, and neuronal activity. A reporter driven by the 1-kilobase sequence upstream of the gene’s transcription start site showed a modest increase from postnatal day 1 to day 7, followed by a sharp increase from day 7 to day 14. At day 14, daily whisker trimming from birth reduced reporter activity, while environmental enrichment from embryonic day 10 to postnatal day 14 increased it. Artificially reducing neuronal activity with Kir2.1 also lowered the reporter signal; increasing activity with mNaChBac raised it. These experiments support bidirectional activity- and experience-dependent regulation of the tested promoter. To investigate how this regulation evolved, the authors compared reporter constructs based on the human ancestral paralogous sequence and the macaque orthologous sequence. Both drove expression, but neither responded to whisker trimming. The human FRMPD2B promoter contains a 303-base-pair AluYe5 retrotransposon insertion with a predicted MEF2 binding site. Deleting this site abolished the developmental increase and experience-dependent response in the reporter assay. Finally, the researchers studied human cortical neurons derived from pluripotent stem cells and transplanted into mouse brains. Two FRMPD2B-targeting shRNAs reduced dendritic length and branching. MEF2C knockdown produced similar effects, supporting a functional link between MEF2 and FRMPD2B. The authors conclude that gene duplication followed by retrotransposon-mediated promoter remodeling gave FRMPD2B an activity-responsive role that may help human cortical neurons develop complex arbors and connections in response to postnatal experience. However, the findings have important limitations: the mouse experiments relied on experimentally introduced FRMPD2B, the promoter assays measured reporter activity rather than the full endogenous regulatory system, and the human-neuron experiment assessed transplanted cells after one month.

How a Human-Specific Gene May Link Experience to Brain Connectivity

The developing brain is shaped not only by its genetic instructions but also by experience. A new study, “The human-specific gene FRMPD2B couples postnatal experience to the expansion of cortical connectivity,” explores a possible molecular link between the two: a gene found in humans that appears to respond to neuronal activity and postnatal experience.

The researchers investigated FRMPD2B, which arose around 2.3 million years ago through a partial duplication of the ancestral gene FRMPD2A. Their findings suggest that FRMPD2B can promote neuronal growth and synaptic connectivity in experimental models, while a distinctive feature of its promoter makes its activity sensitive to experience. The results offer a possible clue to how human cortical circuits develop, though they do not establish that the gene has the same effects in the intact human brain.

A gene with a distinctive pattern of expression

Using long-read RNA sequencing and existing expression datasets, the team found that FRMPD2B produces a short protein of 320 amino acids. They did not detect long FRMPD2A transcripts in the human cortex. FRMPD2 expression was concentrated in excitatory neurons, particularly those involved in connections between cortical regions.

Expression also followed a striking developmental pattern. It began in late gestation, peaked between one and two years after birth, remained elevated through childhood, and declined in adulthood. In macaque cortex, comparable expression was barely detectable. This contrast suggests that FRMPD2B may be associated with a human-specific feature of cortical development.

Effects on neuronal growth and synapses

To investigate what FRMPD2B might do in neurons, the researchers introduced it into upper-layer pyramidal neurons in mouse brains using in utero electroporation. By postnatal day 21, neurons expressing FRMPD2B had longer and more highly branched basal dendrites. Their apical dendrites, however, showed no measurable change.

The team also observed greater dendritic spine density and more presynaptic boutons in cortical layers 2/3 and 5. These structures are associated with synaptic connections. In recordings made at postnatal days 17–19, miniature excitatory postsynaptic currents occurred more frequently in FRMPD2B-expressing neurons. Their amplitude and intrinsic membrane properties were unchanged. Axonal branching also increased at postnatal days 6 and 21.

Together, these results indicate that experimentally expressed FRMPD2B can influence several aspects of neuronal growth and connectivity in mice. They do not, by themselves, show what the gene does at its natural levels in human development.

Experience and activity influence the promoter

The researchers next tested whether the sequence controlling FRMPD2B expression responds to development and experience. A reporter driven by the one-kilobase region upstream of the gene’s transcription start site showed a modest increase from postnatal day 1 to day 7, followed by a sharp rise from day 7 to day 14.

At day 14, daily whisker trimming from birth reduced reporter activity, while environmental enrichment from embryonic day 10 through postnatal day 14 increased it. Experiments that altered neuronal activity showed a similar pattern: reducing activity with Kir2.1 lowered the reporter signal, while increasing activity with mNaChBac raised it. These findings support bidirectional regulation of the tested promoter by activity and experience.

An evolutionary change in gene regulation

To explore how this responsiveness evolved, the team compared reporter constructs based on human and macaque sequences. Both sequences drove expression, but neither responded to whisker trimming. The human FRMPD2B promoter contains an insertion of a 303-base-pair AluYe5 retrotransposon, which includes a predicted binding site for the transcription factor MEF2.

When the researchers deleted this predicted site, the reporter no longer showed the same developmental increase or experience-dependent response. This points to the inserted sequence as an important part of the regulatory difference, although reporter assays cannot capture every feature of the gene’s natural control system.

Evidence from human-derived neurons—and important caveats

The team also studied human cortical neurons derived from pluripotent stem cells and transplanted into mouse brains. Two different shRNAs targeting FRMPD2B reduced dendritic length and branching. Knocking down MEF2C produced similar effects, supporting a functional connection between MEF2 and FRMPD2B.

The conclusions remain provisional. The mouse experiments relied on experimentally introduced FRMPD2B; the promoter studies measured reporter activity rather than the full endogenous regulatory system; and the human-derived neurons were assessed after one month in mouse brains. Further work will be needed to determine how FRMPD2B operates during typical human development and how much it contributes to cortical connectivity.

A possible bridge between genes and experience

Overall, the study proposes a sequence of evolutionary and developmental events: gene duplication created FRMPD2B, and a retrotransposon insertion helped remodel its promoter so that activity and experience could influence its expression. In experimental systems, the gene’s activity is associated with more elaborate neuronal arbors and signs of increased synaptic connectivity. The findings offer a promising hypothesis for how postnatal experience may help shape human cortical circuits, while underscoring the need to test that hypothesis in more direct models of human brain development.

Created on 09 Nov. 2026

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The human-specific gene FRMPD2B couples postnatal experience to the expansion of cortical connectivity

The essentials

Question

Method

Findings

Limitations

Why it matters

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Definitions

How a Human-Specific Gene May Link Experience to Brain Connectivity

A gene with a distinctive pattern of expression

Effects on neuronal growth and synapses

Experience and activity influence the promoter

An evolutionary change in gene regulation

Evidence from human-derived neurons—and important caveats

A possible bridge between genes and experience

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