Review of the molecular development of the thumb: digit primera

Abstract

The thumb, or digit 1, is not a typical digit. In addition to its unusual mobility and function, its formation is also unusual. It is the last digit to form and the most commonly targeted when limb development is disrupted. The thumb domain is defined by the overlapping expression of HOXA13, TBX5, GLI3R, and HOXD13 and, importantly, by an absence of other distal HOXD transcription factors. This brief review, combining developmental biology and clinical genetics, discusses the current understanding of how the thumb domain is established.

Fig. 1

Defining the thumb. The thumb domain is defined by the overlapping expression of HOXA13, TBX5, GLI3R, and HOXD13 and, importantly, an absence of other HOXD transcription factors. Before handplate formation (Carnegie Stg 15), TBX5 is expressed throughout the limb bud; however, as the handplate forms (Carnegie Stg 16), TBX5 expression extends into the presumptive thumb domain (boundary highlighted by yellow dashed lines), HOXA13 is induced, and a region adjacent to the presumptive thumb (PT), the foyer préaxiale primaire (fpp), undergoes programmed cell death (PCD). Processing of GLI3 by SHH sets up an AP gradient of GLI3 repressor (GLI3R) to GLI3 activator, respectively. SHH also regulates the patterning of the distal HOXD transcription factors (HOXD11–13) (Carnegie Stg 18) that physically interact with GLI3 to refine digit identity (the SHH-dependent boundary is highlighted by a purple dashed line). HOXD 10–12 have overlapping expression domains in presumptive digits 2 to 5 but are restricted from the thumb domain. In contrast, HOXD13 is expressed in all of the digit domains including the presumptive thumb. Note the corresponding embryonic days (e 11–13) of the mouse limb from whence these data have been derived.

Fig. 2A–B

The influence of GLI3 on digit formation. This figure illustrates the range of GLI3 influence in the two most common models used in limb development, chick and mouse. In the chicken deletion mutant Oligozeugodactyly (ozd) (A), the limb-specific enhancer of SHH has been deleted. Without SHH, GLI3R function is unopposed and inhibits the formation of the ulna and digits. In contrast, in the GLI3 knockout mouse (B) that lacks GLI3 function, excessive digits are formed (note eight digits) and these digits lack specific AP (radioulnar) identity, most conspicuously the absence of the two phalangeal thumb identity. (Images courtesy of John F. Fallon, PhD, University of Wisconsin, and Maria A. Ros, MD, PhD, Instituto de Biomedicina y Biotechnologia de Cantabria; (A) adapted with permission from Ros et al. [25].).