Pancho, A. | Search bioRxiv

bioRxiv2024

Single-cell profiling of penta- and tetradactyl mouse limb buds identifies mesenchymal progenitors controlling digit numbers and identities

The cellular mechanisms controlling digit numbers and identities have remained elusive. Profiling of wild-type (pentadactyl) and Grem1 tetradactyl mouse limb buds identifies cellular changes affecting two limb bud mesenchymal progenitor (LMP) populations. In mutant limb buds, the anteriorly biased distribution of peripheral LMPs (pLMPs) is lost and the population expanded, while the distal-posterior LMP (dLMP) population is reduced from early stages onward. Analysis of LMP signature genes in wildtype and mutant mouse limb buds with digit loss or gain establishes that pLMPs are positively regulated by BMP signaling, while dLMPs require GREM1-mediated BMP antagonism. dLMPs encompass digit progenitors and altering their population size prefigures changes in digit numbers. The anteriorly biased pLMP distribution is linked to digit asymmetry as loss of this bias in tetradactyl mouse and pig limb buds underlies middle digit symmetry and identity loss. This study indicates that variable spatial Grem1 expression in mutant and evolutionary diversified limb buds tunes BMP activity, impacting both LMP populations in a complementary manner.

developmental biology↗

bioRxiv2024

Altered Socio-Affective Communication and Amygdala Development in mice with Protocadherin10-deficient Interneurons

Autism Spectrum Disorder (ASD) is a group of neurodevelopmental conditions associated with deficits in social interaction and communication, together with repetitive behaviors. The cell adhesion molecule Protocadherin10 (Pcdh10) has been implicated in the etiology of ASD. Pcdh10 is expressed in the nervous system during embryonic and early postnatal development and has been linked to neural circuit formation. Here, we show strong expression of Pcdh10 in the ganglionic eminences and in the basolateral complex of the amygdala at mid and late embryonic stages, respectively. Both inhibitory and excitatory neurons expressed Pcdh10 in the basolateral complex at perinatal stages and genes linked to vocalization behavior were enriched in Pcdh10- expressing neurons in adult mice. To further investigate the involvement of Pcdh10 in neurodevelopment with relevance to ASD, and to assess the functional and behavioral consequences of loss of Pcdh10 in basolateral amygdala interneurons, we combined a ubiquitous and a conditional Pcdh10 knockout mouse model. Conditional knockout of Pcdh10 reduced the number of interneurons in the basolateral complex. Both models exhibited altered developmental trajectories of socio-affective communication through isolation-induced ultrasonic vocalizations in neonatal pups, characterized by increased emission rates in heterozygous pups. Furthermore, acoustic call features were affected and heterozygous conditional knockout pups emitted calls characterized by reduced peak frequencies but increased frequency modulation. Additionally, we identified distinct clusters of call subtypes with specific developmental trajectories, suggesting the vocalization repertoire is extensive and dynamic during early life. The nuanced alterations in socio-affective communication at the level of call emission rates, acoustic call features, and clustering of call subtypes were primarily seen in heterozygous pups of the conditional knockout and less prominent in the ubiquitous Pcdh10 knockout, suggesting that changes in anxiety levels associated with Gsh2-lineage interneurons might drive the observed behavioral effects. Together, this demonstrates that loss of Pcdh10 specifically in interneurons contributes to behavioral alterations in socio-affective communication with relevance to ASD.

neuroscience↗