Postnatal Downregulation of Hedgehog Signaling Suggests a Role in Somatic Growth Deceleration.

FORCINITO P; LUI JCK; BARNES KM; FINKIELSTAIN GP; DOMINICI FP; BARON J

Washington DC, EEUU

Congreso; Endocrine Society 91st Annual Meeting; 2009

Endocrine Society, EEUU

Mammalian somatic growth is rapid in early life but decelerates with age and eventually halts, thus determining adult body size of the species. To maintain body proportions, growth deceleration must occur synchronously in multiple organs. To explore mechanisms, we analyzed changes in gene expression occurring as growth decelerates postnatally in mice by microarray (1). The findings pointed to several regulatory pathways, including hedgehog (Hh) signaling. mRNA levels for Ptch1, Smo, Gli1, Gli2 and Gli3 declined significantly between 1 and 4 w of age in both kidney and lung. Because Hh signaling promotes proliferation, we hypothesized that this decline in Hh signaling contributes to the normal somatic growth deceleration that occurs in multiple tissues. To confirm the microarray findings and to define the time course, real-time PCR was performed with normalization to 18S rRNA. Gli1 mRNA levels declined 13 fold in lung (P < 0.01) and 10 fold in kidney (P < 0.01) between 1 and 4 w of age. Gli1 encodes a transcription factor that participates in Hh signaling, and, additionally, transcription of Gli1 itself requires active Hh signaling. Thus, declining Gli1 mRNA indicates an overall decrease in Hh signaling. Similar declines in expression were seen for other key genes involved in Hh signaling: Shh (ligand), Ptch1 (receptor), Smo, Gli2, Gli3 .In summary, microarray and real-time PCR demonstrated downregulation of Hh signaling in lung and kidney during postnatal growth deceleration, presumably due to decreasing expression of multiple genes involved in signal transduction. Because Hh signaling promotes proliferation, the findings suggest that this downregulation contributes to somatic growth deceleration in mammals and therefore to the mechanisms that determine adult body size.