Abstract
The molecular mechanisms driving brain development at risk in autism spectrum disorders (ASDs) remain mostly unknown. Previous studies have implicated the transcription factor FOXP1 in both brain development and ASD pathophysiology. However, the specific molecular pathways both upstream of and downstream from FOXP1 are not fully understood. To elucidate the contribution of FOXP1-mediated signaling to brain development and, in particular, neocortical development, we generated forebrain-specific Foxp1 conditional knockout mice. We show that deletion of Foxp1 in the developing forebrain leads to impairments in neonatal vocalizations as well as neocortical cytoarchitectonic alterations via neuronal positioning and migration. Using a genomics approach, we identified the transcriptional networks regulated by Foxp1 in the developing neocortex and found that such networks are enriched for downstream targets involved in neurogenesis and neuronal migration. We also uncovered mechanistic insight into Foxp1 function by demonstrating that sumoylation of Foxp1 during embryonic brain development is necessary for mediating proper interactions between Foxp1 and the NuRD complex. Furthermore, we demonstrated that sumoylation of Foxp1 affects neuronal differentiation and migration in the developing neocortex. Together, these data provide critical mechanistic insights into the function of FOXP1 in the developing neocortex and may reveal molecular pathways at risk in ASD.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2039-2055 |
| Number of pages | 17 |
| Journal | Genes and Development |
| Volume | 31 |
| Issue number | 20 |
| DOIs | |
| State | Published - Oct 15 2017 |
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Keywords
- Autism
- Behavior
- Neocortex
- Neurogenomics
- Neuronal migration
- Sumoylation
ASJC Scopus subject areas
- Genetics
- Developmental Biology
Cite this
Foxp1 regulation of neonatal vocalizations via cortical development. / Usui, Noriyoshi; Araujo, Daniel J.; Kulkarni, Ashwinikumar; Co, Marissa; Ellegood, Jacob; Harper, Matthew; Toriumi, Kazuya; Lerch, Jason P.; Konopka, Genevieve.
In: Genes and Development, Vol. 31, No. 20, 15.10.2017, p. 2039-2055.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Foxp1 regulation of neonatal vocalizations via cortical development
AU - Usui, Noriyoshi
AU - Araujo, Daniel J.
AU - Kulkarni, Ashwinikumar
AU - Co, Marissa
AU - Ellegood, Jacob
AU - Harper, Matthew
AU - Toriumi, Kazuya
AU - Lerch, Jason P.
AU - Konopka, Genevieve
PY - 2017/10/15
Y1 - 2017/10/15
N2 - The molecular mechanisms driving brain development at risk in autism spectrum disorders (ASDs) remain mostly unknown. Previous studies have implicated the transcription factor FOXP1 in both brain development and ASD pathophysiology. However, the specific molecular pathways both upstream of and downstream from FOXP1 are not fully understood. To elucidate the contribution of FOXP1-mediated signaling to brain development and, in particular, neocortical development, we generated forebrain-specific Foxp1 conditional knockout mice. We show that deletion of Foxp1 in the developing forebrain leads to impairments in neonatal vocalizations as well as neocortical cytoarchitectonic alterations via neuronal positioning and migration. Using a genomics approach, we identified the transcriptional networks regulated by Foxp1 in the developing neocortex and found that such networks are enriched for downstream targets involved in neurogenesis and neuronal migration. We also uncovered mechanistic insight into Foxp1 function by demonstrating that sumoylation of Foxp1 during embryonic brain development is necessary for mediating proper interactions between Foxp1 and the NuRD complex. Furthermore, we demonstrated that sumoylation of Foxp1 affects neuronal differentiation and migration in the developing neocortex. Together, these data provide critical mechanistic insights into the function of FOXP1 in the developing neocortex and may reveal molecular pathways at risk in ASD.
AB - The molecular mechanisms driving brain development at risk in autism spectrum disorders (ASDs) remain mostly unknown. Previous studies have implicated the transcription factor FOXP1 in both brain development and ASD pathophysiology. However, the specific molecular pathways both upstream of and downstream from FOXP1 are not fully understood. To elucidate the contribution of FOXP1-mediated signaling to brain development and, in particular, neocortical development, we generated forebrain-specific Foxp1 conditional knockout mice. We show that deletion of Foxp1 in the developing forebrain leads to impairments in neonatal vocalizations as well as neocortical cytoarchitectonic alterations via neuronal positioning and migration. Using a genomics approach, we identified the transcriptional networks regulated by Foxp1 in the developing neocortex and found that such networks are enriched for downstream targets involved in neurogenesis and neuronal migration. We also uncovered mechanistic insight into Foxp1 function by demonstrating that sumoylation of Foxp1 during embryonic brain development is necessary for mediating proper interactions between Foxp1 and the NuRD complex. Furthermore, we demonstrated that sumoylation of Foxp1 affects neuronal differentiation and migration in the developing neocortex. Together, these data provide critical mechanistic insights into the function of FOXP1 in the developing neocortex and may reveal molecular pathways at risk in ASD.
KW - Autism
KW - Behavior
KW - Neocortex
KW - Neurogenomics
KW - Neuronal migration
KW - Sumoylation
UR - http://www.scopus.com/inward/record.url?scp=85035353238&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85035353238&partnerID=8YFLogxK
U2 - 10.1101/gad.305037.117
DO - 10.1101/gad.305037.117
M3 - Article
VL - 31
SP - 2039
EP - 2055
JO - Genes and Development
JF - Genes and Development
SN - 0890-9369
IS - 20
ER -