An autoregulatory cell cycle timer integrates growth and specification in chick wing digit development

A fundamental question is how proliferation and growth are timed during embryogenesis. Although it has been suggested that the cell cycle could be a timer, the underlying mechanisms remain elusive. Here we describe a cell cycle timer that operates in Sonic hedgehog (Shh)-expressing polarising region cells of the chick wing bud. Our data are consistent with Shh signalling stimulating polarising region cell proliferation via Cyclin D2, and then inhibiting proliferation via a Bmp2-p27kip1 pathway. When Shh signalling is blocked, polarising region cells over-proliferate and form an additional digit, which can be prevented by applying Bmp2 or by inhibiting D cyclin activity. In addition, Bmp2 also restores posterior digit identity in the absence of Shh signalling, thus indicating that it specifies antero-posterior (thumb to little finger) positional values. Our results reveal how an autoregulatory cell cycle timer integrates growth and specification and are widely applicable to many tissues.

Tbx5 inhibits hedgehog signaling in determination of digit identity

Dominant TBX5 mutation causes Holt-Oram syndrome (HOS), which is characterized by limb defects in humans, but the underlying mechanistic basis is unclear. We used a mouse model with Tbx5 conditional knockdown in Hh-receiving cells (marked by Gli1+) during E8 to E10.5, a previously established model to study atrial septum defects, which displayed polydactyly or hypodactyly. The results suggested that Tbx5 is required for digit identity in a subset of limb mesenchymal cells. Specifically, Tbx5 deletion in this cell population decreased cell apoptosis and increased the proliferation of handplate mesenchymal cells. Furthermore, Tbx5 was found to negatively regulate the Hh-signaling activity through transcriptional regulation of Ptch1, a known Hh-signaling repressor. Repression of Hh-signaling through Smo co-mutation in Tbx5 heterozygotes rescued the limb defects, thus placing Tbx5 upstream of Hh-signaling in limb defects. This work reveals an important missing component necessary for understanding not only limb development but also the molecular and genetic mechanisms underlying HOS.

Are Face-Incongruent Voices Harder to Process?

Based on current integration theories of face–voice processing, the present study had participants process 1,152 videos of faces uttering digits. Half of the videos contained face–voice gender-incongruent stimuli (vs. congruent stimuli in the other half). Participants indicated digit magnitude or parity. Tasks were presented in pure blocks (only 1 task) and in task switching blocks (using colored cues to specify task). The results indicate significant congruency effects in pure blocks, but partially reversed congruency effects in task switching, probably due to enhanced assignment of capacity toward resolving difficult situational demands. Congruency effects did not dissipate over time, ruling out that initial surprise associated with incongruent stimuli drove the effects. The results show that interference between two task-irrelevant person-related dimensions (face/voice gender) can affect processing of a third, task-relevant dimension (digit identity), suggesting greater processing ease associated with more authentic voices (i.e., voices that do not violate face-based expectancies).

Evidence against tetrapod-wide digit identities and for a limited frame shift in bird wings

SummaryIn crown group tetrapods, individual digits are homologized in relation to a pentadactyl ground plan. However, testing hypotheses of digit homology is challenging because it is unclear whether digits develop with distinct and conserved gene regulatory states. Here we show dramatic evolutionary dynamism in the gene expression profiles of digits, challenging the notion that five digit identities are conserved across amniotes. Transcriptomics of developing limbs shows diversity in the patterns of genetic differentiation of digits, although the anterior-most digit of the pentadactyl limb has a unique, conserved expression profile. Further, we identify a core set of transcription factors that are differentially expressed among the digits of amniote limbs; their spatial expression domains, however, vary between species. In light of these results, we reevaluate the frame shift hypothesis of avian wing evolution and conclude that only the identity of the anterior-most digit has shifted position, suggesting a 1,3,4 digit identity in the bird wing.

Digit identity influences numerical estimation in children and adults

Learning the meanings of Arabic numerals involves mapping the number symbols to mental representations of their corresponding, approximate numerical quantities. It is often assumed that performance on numerical tasks, such as number line estimation (NLE), is primarily driven by translating from a presented numeral to a mental representation of its overall magnitude. Part of this assumption is that it is the overall numerical magnitude of the presented numeral, not the specific digits that comprise it, that matter for task performance. Here we ask whether the magnitudes of the presented target numerals drive symbolic number line performance, or whether specific digits influence estimates. If the former is true, estimates of numerals with very similar magnitudes but different digits (such as 399 and 402) should be placed in similar locations. However, if the latter is true, these placements will differ significantly. In two studies (N = 262), children aged 7-11 and adults completed 0-1000 NLE tasks with target values drawn from a set of paired numerals that fell on either side of “Hundreds” boundaries (e.g. 698 and 701) and “Fifties” boundaries (e.g. 749 and 752). Study 1 used an atypical speeded NLE task, while Study 2 used a standard non-speeded NLE task. Under both speeded and non-speeded conditions, specific hundreds digits in the target numerals exerted a strong influence on estimates, with large effect sizes at all ages, showing that the magnitudes of target numerals are not the primary influence shaping children’s or adults’ placements. We discuss patterns of developmental change and individual difference revealed by planned and exploratory analyses.