Genetic Control During Embryonic Development

• Maurice Pescitelli Jr, PhD

• mjpesci@uic.edu

• University of Illinois at Chicago -- College of Medicine

• Department of Anatomy & Cell Biology Dept of Surgery, Division of Pediatric Surgery

Embryonic Development

The construction of an adult from a single cell, the fertilized egg (zygote).

1. Differentiation

A Single Cell, the Fertilized Egg, Gives Rise to Hundreds of Different Cell Types. This Generation of Cellular Diversity Is Called Differentiation.

2. Morphogenesis -- Pattern Formation

Differentiation is carefully orchestrated. The repertoire includes:

• Proliferation• Cell migration• Interactions (Induction)• Epithelial-mesenchymal transformations• Epithelial folding, movement, in- &

evagination, fusion• Apoptosis …

3. Controlled Growth

Dolly and Bonnie

Gilbert, SF (2003) Developmental Biology, 7th ed.

Homeotic mutation: Master Regulatory Genes

Halteres into wings

Gilbert, SF (2003) Developmental Biology, 7th ed.

Homeotic Genes:Master Regulatory Genes

Transformation of L1 into a thoracic vert. by Hoxc-8 KO

Gilbert, SF (2003) Developmental Biology, 7th ed.

Developmental Regulatory genes are Transcription factors

Transcription factors or gene regulatory proteinsare involved in activating or repressing transcription.

TFs act by binding to the control regions of genes or by interacting with other DNA-binding proteins.

Transcription factor Families

• Homeodomain proteins (Hox)• POU• Basic helix-loop-helix• Basic leucine zipper• Zinc finger• Nuclear hormone receptors & their Hormone-

responsive elements• DNA-bending proteins

Homeodomain Proteins

http://www.devbio.com [5.4] (After Pabo and Sauer, 1992)

Genes encoding TFs and resulting phenotype

• Androgen receptor Androgen insensitivity syndrome

• AZF1 Azoospermia• CBFA1 Cleidocranial dysplasia• CSX Heart defects• EMX2 Schizencephaly• Estrogen receptor Growth reg.

problems, …

Genes encoding TFs and resulting phenotype

• Forkhead‑like 15 Thyroid agenesis, cleft palate

• Gl13 Grieg syndrome• HOXA‑13 Hand‑foot‑genital syndrome • HOXD‑13 Polysyndactyly • LMXIB Nail‑patella syndrome • MITF Waardenburg syndrome type 2 • Pax2 Renal‑coloboma syndrome

Genes encoding TFs and resulting phenotype

• PAX3 Waardenburg syndrome type 1 • PAX6 Aniridia • PTX2 Reiger syndrome • PITX3 Congenital cataracts• POU3F4 Deafness and dystonia• SOX9 Campomelic dysplasia, male

sex reversal

Pax6 expression in the mouth parts

Gilbert, SF (2003) Developmental Biology, 7th ed.

Genes encoding TFs and resulting phenotype

• SRY Male sex reversal• TBX3 Schinzel syndrome

(ulna‑mammary syndrome)• TBX5 Holt‑Oram syndrome • TCOF Treacher‑Collins syndrome • TWIST Seathre‑Chotzen syndrome • WTI Urogenital anomalies

What turns TFs on?

Back to the fruit fly

• In Drosophila, patterning of denticles on each segment is under genetic control.

• A mutation disrupts this patterning and results in a continuous lawn of denticles suggesting the “spines of a hedgehog” to the discoverers.

• Drosophila hh encodes a secreted peptide (morphogen) responsible for patterning in the wing as well as other parts of the fly.

Normal Denticle pattern

Alexandre C, et al 1999 Development 126:5689-98

Hedgehog

Action of Signaling molecules – Paracrine factors

• Inducing factors controlling the form of a developing organ

• Mitogen regulating cell proliferation

• Morphogen acting in a dose-dependent way to pattern the cell fates within a target field

In situ hybridization of shh gene expression in 3-day chick embryo

Gilbert, SF (2003) Developmental Biology, 7th ed.

Regulation of Spinal Cord Development

Sadler, 9th ed.

Sadler, 9th ed.

Families of Signaling Molecules

• Hedgehog families (Indian, Desert, Sonic)

• Wnt

• Fibroblast growth factor

• TGF-beta superfamily

• Platelet-derived growth factor

• Ephrin

Summary

• Master developmental regulatory genes are Transcription Factors

• Signaling (paracrine) factors activate the TFs

• These are used over and over in a modular fashion during development: Their effects depend on the position and history of the cells in which they are expressed.

Selected Bibliography

• Texts

– Scott F. Gilbert. 2003. Developmental Biology, 7th Ed. Sinaur Associates. http://www.devbio.com is an associated site with useful supplementary material.

– T. W. Sadler. 2004. Langman’s Medical Embryology, 9th Ed. Lippincott Williams and Wilkins.

• Recent Reviews

– Veraksa A, et al. 2000. Minireview: Developmental Patterning Genes and Their Conserved Functions: From Model Organism to Humans. Molecular Genetics and Metabolism 69:85-100

– Ingham and McMahon 2001. Hedgehog signaling in animal development: paradigms and principles. Genes & Development 15: 3059-3087.

– Kim, Kim, and Hui. 2001. The VACTERL Association: lessons from the Sonic Hedgehog pathway. Clin. Genet. 59:306-315.

– The May 15, 2003 issue of Nature has a special section on bone and cartilage with 8 reviews that address many of the topics I have tried to cover. The next slide is a figure from one of them.

Figure 3 Mouse and human phenotypes caused by mutations affecting skeletal patterning and differentiation. The grouping of the disorders reflects the different origins of the progenitor cells in the craniofacial (cranial neural crest), axial (somites) and limb skeleton (lateral plate mesoderm). Only disorders discussed in the text are listed. The responsible genes are in parentheses after the names of the syndromes. ELAZAR ZELZER1 AND BJORN R. OLSEN1 Nature 423, 343 - 348 (2003); The genetic basis for skeletal diseases. Harvard Medical School, Department of Cell Biology, 240 Longwood Avenue, Boston, Massachusetts 02115, USA